臺灣博碩士論文加值系統

無中文關鍵字

Triple negative breast cancers (TNBC) possess cell dedifferentiation characteristics, carry out activities connate to those of cancer stem cells (CSCs) and are associated with increased metastasis, as well as, poor clinical prognosis. The regulatory mechanism of this highly malignant phenotype is still poorly characterized. Accruing evidence support the role of non-coding RNAs (ncRNAs) as potent regulators of CSC and metastatic gene expression, with their dysregulation implicated in tumorigenesis and disease progression. In this study, we investigated TNBC metastasis, metastasis-associated genes and potential inhibitory mechanisms. Compared with other breast cancer types, the highly metastatic MDA-MB-231 cells concurrently exhibited increased expression levels of Lysine-specific demethylase 5B protein (KDM5B) and long non-coding RNA (lncRNA), MALAT1, suggesting their functional association. KDM5B-silencing in the TNBC cells correlated with the upregulation of hsa-miR-448 and led to suppression of MALAT1 expression with decreased migration, invasion and clonogenic capacity in vitro, as well as, poor survival in vivo. This projects MALAT1 as a mediator of KDM5B oncogenic potential and highlights the critical role of this microRNA, lncRNA and histone demethylase in cancer cell motility and metastatic colonization. Increased expression of KDM5B correlating with disease progression and poor clinical outcome in breast cancer was reversed by hsa-miR-448. In parallel experiments, Pre-treatment of the TNBC cells with 10μM Ovatodiolide (Ova) 24 h before Doxorubicin (Doxo) administration increased the Doxo anticancer effect (IC50 1.3μM) compared to simultaneous treatment with Doxo (IC50 3.4μM), or Doxo alone (IC50 5.0μM). The intracellular accumulation of Doxo was lowest in the Ova pre-treated cells at all Doxo concentrations compared to Doxo alone or simultaneously treated cells. The cell cycle analysis of MDA-MB-231 cells treated concurrently with 2.5μM Ova and 1.25μM Doxo, showed increased percentage of cells arrested at G0/G1 compared to the Doxo-only group; however, pre-treatment with same concentration of Ova 24 h before Doxo treatment showed greater tumor growth inhibition with a 2.4-fold increased percentage of cells in G0/G1 arrest, greater Doxo-induced apoptosis, and significantly reduced intracellular Doxo accumulation. Additionally, Ova-sensitized TNBC cells lost their cancer stem cell-like phenotype, as evidenced by significant dissolution, necrosis or terminal differentiation of formed mammospheres. Taken together, our findings demonstrate the critical role of KDM5B and its negative regulator hsa-miR-448 in TNBC metastasis and progression. The disruption of KDM5B-MALAT1 signalling axis and associated activities in TNBC cells after Ova sensitization and upregulation of hsa-miR-448, projects them as putative therapeutic factor for selective eradication of TNBC cells.

Graduate Thesis Certification..........................ii
Graduate Student Thesis Publication Agreement.........iii
Graduate Thesis Defense Confidentiality Agreement......iv
Declaration............................................vi
Acknowledgements......................................vii
Table of Contents....................................viii
List of Tables........................................xii
List of Figures.......................................xiv
Abstract ..............................................1
Thesis Overview
Thesis Problem Definition......2
Thesis Rationale...............2
Thesis Hypotheses..............3
Thesis Generic Aim(s)..........4
Thesis Experimental Design.....4
Chapter 1: Introduction
1.1: The Normal Breast: Embryology, Morphology and Physiology.............................5
1.2: Breast Cancer as a Polyetiologic Pathology ............................................6
1.2.1: Multifactorial disorder with polygenic association.................................7
1.2.2: The role of CSCs in the pathogenesis of breast cancer .....................................9
1.2.3: Breast cancer stem cells (BCSCs): functional morphology and clinical correlation .......10
1.3:  Molecular and Biological Heterogeneity of Breast Cancer .....................................12
1.3.1:  Bioclinical characterization and molecular stratification of breast cancer.............12
1.3.2:  Gene expression profiling of breast cancer ...............................................14
1.3.3:  The basal-like triple negative breast cancer ...............................................16
1.4:  Current Therapeutic Strategy and Modalities ...........................................17
Chapter 2:  Epigenetic Signatures in Breast Cancer - Diagnostic, Prognostic and Therapeutic Implications
2.1: Non-coding Ribonucleic Acids (ncRNAs) - definition, formation, regulation and function.
2.1.1:  Small/Short ncRNAs
2.1.2:  Large/Long ncRNAs
2.1.3:  Non-coding RNAs in tumorigenicity and oncogenesis
2.1.4:  The Divergent Role of ncRNAs in Breast Cancer
2.2:  Histone Modifications - mechanisms and oncogenic implications
2.2.1:  Histone modification in Breast Cancer
2.3:  Differential Epigenetic Signatures in TNBCs
Chapter 3: Novel Epigenetic Players in Breast Cancer Game of Aggression
3.1: Aberrant KDM5B Expression Promotes Aggressive Breast Cancer through MALAT1 Overexpression and Downregulation of hsa-miR-448
3.1.1: Introduction
3.1.2: Results
3.1.2.1: Upregulation of KDM5B expression in human breast cancer tissues and cell lines.
3.1.2.2: High KDM5B expression is significantly associated with clinical outcome in breast carcinoma, in vivo
3.1.2.3: KDM5B enhances the proliferation and maintenance of aggressive breast cancer cells malignant phenotype.
3.1.2.4: Silencing of KDM5B markedly reduced migration and invasive potential of TNBC cells.
3.1.2.5: Forced KDM5B expression induced tumorigenicity, enhanced migration, and acquisition of CSC-like phenotype in non- tumorigenic MCF-10A breast cancer cell line.
3.1.2.6: KDM5B induces the expression of MALAT1 and its effector metastasis- associated genes in triple negative breast carcinoma cells.
3.1.2.7: KDM5B interacts with MALAT1 to modulate its expression in triple negative breast carcinoma cells and consequently facilitate invasion and associated metastatic activities.
3.1.2.8: KDM5B is a functional target of hsa-miR-448, thus, aberrant downregulation of the later in KDM5B-overexpressing triple negative breast carcinoma tissues and cell lines.
3.1.2.9: Discussion
3.1.2.10: Conclusion
Chapter 4: Creating a Level Playing Field in Breast Cancer Therapy - The Phytochemical Connection
4.1:  Introduction
4.2:  Ovatodiolide inhibits MDA-MB-231 cell proliferation by downregulating KDM5B expression in a dose-dependent manner
4.3:  KDM5B is a druggable gene
4.4:  Ovatodiolide inhibits KDM5B-modulated TNBC stem cell-like phenotype
Chapter 5: Ovatodiolide sensitizes aggressive breast cancer cells to doxorubicin, eliminates their cancer stem cell-like phenotype, and reduces doxorubicin-associated toxicity
5.1:  Introduction
5.2:  Results
5.2.1:  Ovatodiolide augments the antiproliferative activity of doxorubicin
5.2.2:  Induction of apoptosis in ovatodiolide–doxorubicin treated TNBC cells
5.2.3:  Pre-treatment with ovatodiolide reduces intracellular accumulation of doxorubicin
5.2.4:  Sensitization with ovatodiolide before doxorubicin treatment significantly ameliorates intracellular doxorubicin accumulation and toxicity in non-tumorigenic breast cells
5.2.5:  Pre-treatment with ovatodiolide significantly enhances inhibition of in vitro cell migration and colony formation
5.2.6:  Doxo alone or simultaneous Ova–Doxo treatment favors G2/M phase arrest, but sequential Ova–Doxo administration induces arrest in S-phase and G0/G1-phase of MDA-MB-231 cell cycle progression
5.2.7:  Sensitization with ovatodiolide before doxorubicin treatment abolished the cancer stem cell-like phenotype of TNBC cells
5.2.8:  Discussion
5.2.9:  Conclusion
Chapter 6: Research Methodology
6.1:  Materials and Methods for Chapter 3
6.2:  Materials and Methods for Chapter 4 & 5
Chapter 7: Thesis Synopsis
7.1:  Thesis Pictorial Synopsis
7.2:  Contribution of this Study
7.3:  Limitations of the Study
7.4:  Perspectives for Future Research
Epilogue
Bibliography
Appendixes
Publication Lists
Vita
Copyright Clearance Licence(s)
List of Tables
Table 1.1 Tanner’s Phases of Breast Development 5
Table 1.2 Broad Molecular Classification of Breast Cancer 15
Table 1.3 Cellular Function of Selected Breast Cancer-Related Genes 15
Table 1.4 Pathological Features of Triple Negative and Basal-Like Breast
Cancers 17
Table 1.5 Targeted Treatment Approaches for Metastatic TNBC 18
Table 1.6 Neoadjuvant Platinum-Based Chemotherapy Trials for TNBC 19
Table 2.1 Non-Coding RNAs: Classification and Numenclature 21
Table 2.2 MicroRNAs Associated with Cancer 24
Table 2.3 LncRNAs Implicated in Human Cancer and Metastatis 25
Table 2.4 MiRNAs Differentially Expressed Between Breast Carcinoma
and Normal Breast Tissue 26
Table 2.5 Normal and Tumor Breast Tissue Class Predictor miRNAs 27
Table 2.6 Differentially Expressed miRNAs Associated with Invasive
Breast Cancer Bio-Pathologic Features 28
Table 2.7 Twenty-Five Differntially Expressed miRNAs between TNBCs
and Adjacent Normal Breast Tissue 31
Table 2.8 Polycistronic miRNA Clusters Harboring Deregulated miRNAs
between TNBCs and Adjacent Normal Breast Tissue 32
Table 2.9 Histone Modification Genes Altered in Various Human Cancers 38
Table 2.10 Epigenetic Signature of Triple Negative Tumors 40
Table 3.1 Univariate and Multivariate Analyses using Cox Proportion
Hazards Model of Overall Survival of All Hormone Negative
Breast Cancers 48
Table 3.2 Quantification of GAPDH-normalized Average Gene Expression
in MCF10A OE, MDA-MB-231WT and MDA-MB-231KD Cells
with Estimated Fold Change in Expression 53
Table 4.1 List of selected phytochemicals with demonstrated anticancer
potential via epigenetic modulation of known oncofactors 66
Table 4.2 List of selected active compounds that inhibit the demethylase
activity of KDM5B 67
Table 5.1 Clonal Analysis of TNBC Cell Line MDA-MB-231-derived
Colonies 83
Table 5.2 Differential IC50 for Doxo only, Ova-Doxo Simultaneous and
Sequential Treatment of TNBC Cells 87

List of Figures
Figure 1.1.1 Morphology of the Normal Breast 6
Figure 1.2.1 Malignant Transformation of Normal Breast Cancer Cells 7
Figure 1.2.2 Schematic Model of Cancer Polyetiologism 8
Figure 1.2.3 Functional Morphology and Clinical Correlation of Breast
Cancer Stem Cells 11
Figure 2.1.1 Schematic Representation of miRNA Biosynthesis 22
Figure 2.1.2 Cluster Analysis and PAM Prediction in Breast Cancer and
Normal Breast Tissues 29
Figure 2.1.3 Polycistronic miR clusters that preferentially habour
dysregulated miRs in TNBC 30
Figure 2.2.1 Functional Consequences of Histone Onco-Modifications 35
Figure 2.2.2 Chromatin Structure and Histone Onco-Modifications 36
Figure 2.2.3 Histone-Modifying Enzymes Deregulated in Cancer 37
Figure 3.1.1 KDM5B’s Cup of Death 42
Figure 3.1.2 Upregulation of KDM5B Expression in Human Breast Cancer
Tissues and Cell Lines 45
Figure 3.1.3 Correlation of KDM5B Expression with Patients’ Survival 47
Figure 3.1.4 KDM5B Enhances the Proliferation and Maintenance of TNBC
cells Malignant Phenotype 49
Figure 3.1.5 Silencing of KDM5B Markedly Reduced the Migration and
Invasive Potential of TNBC Cells 50
Figure 3.1.6 Forced KDM5B Expression Induced Tumorigenicity and
Enhanced Acquisition of CSC-like Phenotype in Non-
Tumorigenic Cells 52
Figure 3.1.7 GAPDH-Normalized Relative Expression of KDM5B,
MALAT1, SNAIL, Vimentin and Hsa-miR-448 in Breast Cell
Lines 53
Figure 3.1.8 KDM5B Induces the Expression of MALAT1 and Its Effector
Metastasis-Associated Genes in TNBC Cells 55
Figure 3.1.9 KDM5B is Preferentially Expressed in TNBC Tissues 56
Figure 3.1.10 KDM5B Interacts Directly with MALAT1 to Modulate Its 58
Expression in TNBC Cells 60
Figure 3.1.11 KDM5B is a Functional Target of Hsa-miR-448 in TNBC Cells
Figure 4.1 Empirical Chemical Structures for Carboxylic Acid and its
Derivatives 68
Figure 4.2 Ovatodiolide inhibits Cell Proliferation in a KDM5B expression
level-dependent manner 69
Figure 4.3 Probing the Interaction between Ovatodiolide and KDM5B using
the Bioinformatics Approach 70
Figure 4.4 Ova Treatment Markedly Reduced the Formation of MDA-MB-
231Mammospheres 71
Figure 5.1.1 Ovatodiolide Augments the Antiproliferative Activity of
Doxorubicin 76
Figure 5.1.2 Ovatodiolide-Doxorubicin Combination Therapy Induces
Apoptosis in Treated TNBC Cells 78
Figure 5.1.3 Pretreatment with Ovatodiolide Reduces Intracellular
Accumulation of Doxorubicin and Diminishes Toxicity to Non-
Tumorigenic Cells 80
Figure 5.1.4 Pretreatment with Ovatodiolide Significantly Enhances Inhibition
of in vitro Migration and Colony Formation 82
Figure 5.1.5 Flow Cytometric Cell Cycle Analysis in TNBC Cell Lines 84
Figure 5.1.6 Sensitization with Ovatodiolide before Doxorubicin Treatment
Abolished Cancer Stem Cell-Like Phenotype of TNBC Cells 85
Figure 5.1.7 Mammosphere Formation and Survival Assay Showing Effects
of Different Treatment Regimens of TNBC 86

Thesis Overview
[1]Siegel R, Naishadham D, Jemal A. (2012). Cancer statistics, 2012. CA: Cancer J Clin 2012;62(1):10–29.
[2]Pogoda K, Niwinska A, Murawska M, Pienkowski T. (2013). Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol 30(1):388. doi: 10.1007/s12032-012-0388-4.
[3]Verma S, Provencher L, Dent R. (2011). Emerging trends in triple-negative breast cancer in Canada: A survey. Curr Oncol 18(4)
[4]Paolicchi E, Crea F, Farra WL, Green JE, Danesi R. (2013). Histone lysine demethylases in breast cancer. Crit Rev Oncol Hematol 86(2): 97–103
[5]Huang Y, Vasilatos SN, Boric L, Shaw PG, Davidson NE. (2012). Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Research and Treatment 131(3):777–89. doi: 10.1007/s10549-011-1480-8.
[6]Lim S. Janzer A, Becker A, Zimmer A, Schule R, Buettner R, Kirfel J. (2009). Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis 2010; 31(3):512–20
[7]Aragon-Ching JB, Zujewski JA. (2007). CNS metastasis: an old problem in a new guise. Clin Cancer Res 13(6): 1644-7
[8]Bamodu OA, Huang WC, Lee WH, Wu A, Wang LS, Hsiao M, Yeh CT, Chao TY. Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of hsa-miR-448. BMC Cancer 2016 Feb 25; 16: 160. doi:10.1186/s12885-016-2108-5.
Main Text
[1]Skandalakis J.E (2009) Embryology and Anatomy of the Breast. In Breast Augmentation: Principles and Practice. (pp 3-24). Berlin Heidelberg. Springer. doi: 10.1007/978-3-540-78948-2\_{}1.
[2]Tanner JM., Whitehouse RH.1976. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Archives of disease in childhood, 51(3), 170-179.
[3]Hanahan D. 2014. Rethinking the war on cancer. Lancet 383(9916):558-563 doi. 10.1016/S0140-6736(13)62226-6
[4]Knudson AG. 2002. Cancer genetics. Am J Med Gen 111(1):96-102
[5]Vogelstein B, Kinzler KW. 2004. Cancer genes and the pathway they control. Nat Med 10(8):789
[6]Anand P, Kunnumakara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB. 2008. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 25(9):2097-2116 doi: 10.1007/s11095-008-9661-9
[7]Belpomme D., Irigaray P., Hardell L., Clapp R., Montagnier L., Epstei S., Sasco A J. 2007. The multitude and diversity of environmental carcinogens. Environmental Research, 105(3), 414-429.
[8]Henderson BE, Bernstein L, Ross RK (2000). Hormones and the Etiology of Cancer. In Bast RC, Kufe DW, Pollock RE et al. Holland-Frei Cancer Medicine (5th ed.). Hamilton, Ontario B.C. Decker. ISBN 1-55009-113-1.
[9]Huo D, Ikpatt F, Khramtsov A, Dangou JM, Nanda R, Dignam J, Zhang B, Grushko T, Zhang C, Oluwasola O, Malaka D, Malami S, Odetunde A, Adeoye AO,Iyare F, Falusi A, Perou CM, Olopade OI. 2009. Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J Clin Oncol.27 (27):4515-21. doi: 10.1200/JCO.2008.19.6873.
[10]Roa BB. et al. 1996. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14(2): 185-187.
[11]Bird A. 2007. Perceptions in epigenetics. Nature 447(7143):396-398.
[12]Egger G, Liang G, Aparicio A, Jones PA. 2004. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429(6990):457-63
[13]Ye J, Ai X, Eugeni EE, Zhang L, Carpenter LR, Jelinek MA, Freitas MA, Parthun MR. 2005. Histone H4 lysine 91 acetylation a core domain modification associated with chromatin assembly. Mol. Cell 18(1), 123–30.
[14]Xu F, Zhang K, Grunstein M. 2005. Acetylation in histone H3 globular domain regulates gene expression in yeast. Cell 121(3), 375–85.
[15]Nathan D, Ingvarsdottir K, Sterner DE, Bylebyl GR, Dokmanovic M, Dorsey JA, Whelan KA, Krsmanovic M, Lane WS, Meluh PB, Johnson ES, Berger SL. 2006. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev. 20(8), 966–76
[16]Zhang Y, Griffin K, Mondal N, Parvin JD. 2004. Phosphorylation of histone H2A inhibits transcription on chromatin templates. J. Biol. Chem. 279(21), 21866–72.
[17]Zhu B, Zheng Y, Pham AD, Mandal SS, Erdjument-Bromage H, Tempst P, Reinberg D. 2005. Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. Mol. Cell 20(4), 601–11.
[18]Chew YC, Camporeale G, Kothapalli N, Sarath G, Zempleni J. 2006. Lysine residues in N-terminal and C-terminal regions of human histone H2A are targets for biotinylation by biotinidase. J. Nutr. Biochem. 17(4), 225–33
[19]Esteller, M. 2011. Non-coding RNAs in human disease. Nature Reviews Genetics, 12(12), 861-874.
[20]Mielnicki LM, Asch HL, Asch BB. 2001. Genes, chromatin, and breast cancer: an epigenetic tale. J Mammary Gland Biol Neoplasia, 6(2), 169-182.
[21]Clevers, H. (2011). The cancer stem cell: premises, promises and challenges. Nature medicine, 313-319.
[22]Aisenberg AC., Finkelstein DM., Doppke KP., Koerner FC., Boivin JF., Willett CG. (1997). High risk of breast carcinoma after irradiation of young women with Hodgkin’s disease. Cancer, 79: 1203–1210
[23]Tokunaga, M., Norman Jr., J. E., Asano, M., et al. (1979). Malignant breast tumors among atomic bomb survivors, Hiroshima and Nagasaki, 1950-74. Journal of the National Cancer Institute 62: 1347–1359.
[24]Smith GH. (2005). Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development, 132: 681–687.
[25]Pierce GB. (1977). Neoplastic stem cells. Advances in Pathobiology. 6: 141–152.
[26]Pierce GB, Nakane PK, Martinez-Hernandez A, Ward JM. (1977). Ultrastructural comparison of differentiation of stem cells of murine adenocarcinomas of colon and breast with their normal counterparts. Journal of the National Cancer Institute. 58: 1329–1345.
[27]Hirschmann-Jax C, Foster AE, Wulf GG, et. al. (2004). A distinct side population of cells with high drug efflux capacity in human tumor cells. Proceedings of the National Academy of Sciences of the United States of America. 101: 14228–14233.
[28]Bao L, Hague A, Jackson K, Hazari S, Moroz K, Jetly R, Dash S. 2011. Increased expression of P-glycoprotein is associated with doxorubicin chemoresistance in the metastatic 4T1 breast cancer model. Am J Pathol, 178(2): 838-852
[29]Dontu G, El-Ashry D, Wicha MS. (2004). Breast cancer, stem/progenitor cells and the estrogen receptor. Trends in Endocrinology and Metabolism. 15: 193–197.
[30]Dontu G, Abdallah WM, Foley JM., et al. (2003). In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes &{} Development. 17: 1253–1270.
[31]Lin H. (2002). The stem-cell niche theory: lessons from flies. Nature Rev. Genet. 3: 931–940
[32]Reya T, Morrison SJ, Clarke MF, Weissman IL. (2001). Stem cells, cancer, and cancer stem cells. Nature 414: 105-111
[33]Arendt LM, Keller PJ, Skibinski A, Goncalves K, Naber SP, Buchsbaum RJ, Gilmore H, Come SE, Kuperwasser C. (2012). Anatomical localization of progenitor cells in human breast tissue reveals enrichment of uncommitted cells within immature lobules. Breast Cancer Research, 16:453-469
[34]Gjorevski N, Nelson CM. (2011). Integrated morphogenic signalling of the mammary gland. Nature Rev Mol Cell Biol. 12: 581-593. doi:10.1038/nrm3168
[35]Polyak K. (2007). Breast cancer: origins and evolution. J. Clin. Invest. 117(11):3155–3163. doi:10.1172/JCI33295.
[36[Vargo-Gogola T, Rosen JM. (2007). Modelling breast cancer:one size does not fit all. Nature Reviews Cancer. 7:659-672. doi:10.1038/nrc2193
[37]Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 98(19):10869–10874.
[38]Polyak K. (2011). Heterogeneity in breast cancer. J Clin Invest. 121(10):3786–3788. doi:10.1172/JCI60534.
[39]Darwin C. (1859). On the origin of species. http://www.gutenberg.org/files/1228/1228-h/1228-h.htm accessed 05.04.2015
[40]Nowell PC. (1976). The clonal evolution of tumor cell populations. Science 194:23 - 28.
[41]Merlo LM, Pepper JW, Reid BJ, Maley CC. (2006). Cancer as an evolutionary and ecological process. Nat Rev Cancer 6:924 - 935.
[42]Ichim CV, Wells RA (2006) First among equals: the cancer cell hierarchy. Leuk Lymphoma 47:2017–2027
[43]Pardal R, Clarke MF, Morrison SJ. (2003). Applying the principles of stem cell biology to cancer. Nat Rev Cancer 3:895-902.
[44]Polyak K, Hahn WC. (2006). Roots and stems: Stem cells in cancer. Nat Med 12:296 300.
[45]Hill RP (2006) Identifying cancer stem cells in solid tumors: Case not proven. Cancer Res 66 (4):1891–1895
[46]Tan BT, Park CY, Ailles LE, Weissman IL. (2006). The cancer stem cell hypothesis: A work in progress. Lab Invest 86:1203-1207
[47]Tysnes BB, Bjerkvig R. (2007). Cancer initiation and progression: involvement of stem cells and the microenvironment. Biochim Biophys Acta 1775: 283-297. doi:10.1016/j.bbcan.2007.01.001.
[48]Feinberg AP, Ohlsson R, Henikoff S. (2006). The epigenetic progenitor origin of human cancer. Rev Genet. 7:21–33.
[49]Li L, Neaves WB. (2006). Normal Stem Cells and Cancer Stem Cells: The Niche Matters. Cancer Res 66(9): 4553-4557 doi:10.1158/0008-5472.CAN-05-3986
[50]Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983 - 3988.
[51]Farmer, P., Bonnefoi, H., Becette, V., Tubiana-Hulin, M., Fumoleau, P., Larsimont, D., MacGrogan, G., Bergh, J., Cameron, D., Goldstein, D., Duss, S., Nicoulaz, A.-L., Brisken, C., Fiche, M., Delorenzi, M., and Iggo, R. (2005) Identification of molecular apocrine breast tumours by microarray analysis. Oncogene, 24, 4660-4671.
[52]Paik, S., Shak, S., Tang, G., Kim, C., Baker, J., Cronin, M., Baehner, F. L., Walker, M. G., Watson, D., Park, T., Hiller, W., Fisher, E. R., Wickerham, D. L., Bryant, J., Wolmark, N. (2004) A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer. N. Engl. J. Med.351: 2817-2826.
[53]Habel, L A., Shak, S., Jacobs, M. K., Capra, A., Alexander, C., Pho, M., Baker, J., Walker, M., Watson, D., Hackett, J., Blick, N T., Greenberg, D., Fehrenbacher, L., Langholz, B., Quesenberry, C. P. (2006). A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 8: R25.
[54]Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA., et al. (2000) Molecular portraits of human breast tumours. Nature 406: 747 - 752
[55]Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM. (2006) Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 19(2): 264 - 271
[56]Shien T, Tashiro T, Omatsu M, Masuda T, Furuta K, Sato N, Akashi-Tanaka S, Uehara M, Iwamoto E, Kinoshita T, Fukutomi T, Tsuda H, Hasegawa T. (2005) Frequent overexpression of epidermal growth factor receptor (EGFR) in mammary high grade ductal carcinomas with myoepithelial differentiation. J Clin Pathol. 58(12):1299 - 1304
[57]Palacios J, Benito N, Pizarro A, Suárez A, Espada J, Cano A, Gamallo C. (1995) Anomalous expression of P-cadherin in breast carcinoma. Correlation with E-cadherin expression and pathological features. Am J Pathol 146(3):605 - 612
[58]Abd El-Rehim DM, Pinder SE, Paish CE, Bell J, Blamey RW, Robertson JF, Nicholson RI, Ellis IO. (2004) Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol 203(2):661 - 671
[59]Carey L, Winer E, Viale G, Cameron D, Gianni L. (2010) Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol. 7(12): 683 - 92.
[60]Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET. (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100:10393 - 10398
[61]Shin BK, Lee Y, Lee JB, Kim HK, Lee JB, Cho SJ, Kim A.(2008) Breast carcinomas expressing basal markers have poor clinical outcome regardless of estrogen receptor status. Oncol Rep. 19(3):617-25.
[62]Turner N, Tutt A, Ashworth A.(2004) Hallmarks of ''BRCAness'' in sporadic cancers. Nat Rev Cancer. 4(10):814-9.
[63]Korsching E, Packeisen J, Agelopoulos K, Eisenacher M, Voss R, Isola J, van Diest PJ, Brandt B, Boecker W, Buerger H. (2002) Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab Invest. 82(11):1525-33.
[64]Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. (2007) Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 109(9):1721-8.
[65]Stead LA, Lash TL, Sobieraj JE, Chi DD, Westrup JL, Charlot M, Blanchard RA, Lee JC, King TC, Rosenberg CL.(2009) Triple-negative breast cancers are increased in black women regardless of age or body mass index. Breast Cancer Res. 11(2):R18
[66]Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. (2008) Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer. 113(10):2638-45.
[67]Banerjee S, Reis-Filho JS, Ashley S, Steele D, Ashworth A, Lakhani SR, Smith IE. (2006) Basal-like breast carcinomas: clinical outcome and response to chemotherapy. J Clin Pathol. 59(7):729-35.
[68]Rhodes A, Jasani B, Balaton AJ, Barnes DM, Miller KD. (2000) Frequency of oestrogen and progesterone receptor positivity by immunohistochemical analysis in7016 breast carcinomas : correlation with patient age, assay sensitivity,threshold value, and mammographic screening. J Clin Pathol 53 : 688 – 696.
[69]Rakha EA, El-Sayed ME, Green AR, Paish C, Powe DG, Gee J, et al.(2007) Biologic and clinical characteristics of breast cancer with single hormone receptor positive phenotype. J Clin Oncol 25: 4772–8.
[70]Shao W, Brown M.(2004) Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy. Breast Cancer Res 6: 39–52.
[71]Ross JS, Fletcher JA, Bloom KJ, Linette GP, Stec J, Symmans WF, et al.(2004) Targeted therapy in breast cancer: the HER-2/neu gene and protein. Mol Cell Proteomics 3: 379–98.
[72]Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 13:2329–34.
[73]Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, et al. (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–85.
[74]Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 100: 8418 8423.
[75]Rakha EA, Tan DS, Foulkes WD, Ellis IO, Tutt A, Nielsen TO, et al. (2007) Are triple-negative tumours and basal-like breast cancer synonymous? Breast Cancer Res. 9:404.
[76]Rakha EA, Putti TC, Abd El-Rehim DM, Paish C, Green AR, Powe DG, et al. (2006) Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol 208: 495–506.
[77]Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10: 5367–74.
[78]Kim MJ, Ro JY, Ahn SH, Kim HH, Kim SB, Gong G. (2006) Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum Pathol 37: 1217–26.
[79]Tommiska J, Bartkova J, Heinonen M, Hautala L, Klipivaara O, Eerola H, et al. (2008) The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2 deficient and ER/PR/ERBB2-triple-negative breast cancer. Oncogene 27: 2501–6.
[80]von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. (2012) Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes. J Clin Oncol 30: 1796 - 1804
[81]Hayes DF, Thor AD, Dressler LG, Weaver D, Edgerton S, Cowan D, et al. (2007) HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med. 357:1496–506.
[82]Tan DSP, Marchio C, Jones RL, Savage K, Smith IE, Dowsett M, Reis JS. (2008) Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat 111 (1): 27-44
[83]Falo C, Moreno A, Varela M, Lloveras B, Figueras A, Escobedo A. (2007) HER-2/neu status and response to CMF: retrospective study in a series of operable breast cancer treated with primary CMF chemotherapy. J Cancer Res Clin Oncol 133: 423 - 429
[84]Rodríguez-Pinilla SM, Sarrió D, Honrado E, Hardisson D, Calero F, Benitez J, Palacios J.(2006). Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res 12: 1533–1539
[85]Cheang M, Chia SK, Tu D, Jiang S, Shepherd LE, Pritchard KI, et al. (2009) Anthracyclines in basal breast cancer: the NCIC-CTG trial MA5 comparing adjuvant CMF to CEF. J Clin Oncol 27(15s): a519
[86]Sirohi B, Arnedos M, Popat S, Ashley S, Nerurkar A, Walsh S, et al. (2008) Platinum-based chemotherapy in triple-negative breast cancer. Ann. Oncol. 19, 1897 - 1852
[87]Mattick JS. (2001) Non-coding RNAs: the architects of eukaryotic complexity. EMBO Reports 2:986–991
[88]Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. (2001) The sequence of the human genome. Science 291:1304–1351.
[89]Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921.
[90]Hanada K, Zhang X, Borevitz JO, Li WH, Shiu SH. (2007) A large number of novel coding small open reading frames in the intergenic regions of the Arabidopsis thaliana genome are transcribed and/or under purifying selection. Genome Res. 17(5):632-40.
[91]Kondo T, Plaza S, Zanet J, Benrabah E, Valenti P, Hashimoto Y, et al. (2010) Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis. Science 329 (5989): 336-9. doi: 10.1126/science.1188158.
[92]Spizzo R, Almeida MI, Colombatti A, Calin GA. (2012) Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene 31(43):4577-87. doi: 10.1038/onc.2011.621.
[93]Redis RS, Calin GA. (2014) Beyond miRNAs: Role of other noncoding RNAs in cancer. In M. Fabbri (Ed.), Non-coding RNAs and cancer. (illustrated ed., pp 248 - 264). New York: Springer Science and Business Media, LLC
[94]Ambros V. The functions of animal microRNAs. (2004) Nature 431: 350–355
[95]Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. (2004) Cell 116: 281–297
[96]Rajewsky N. microRNA target predictions in animals.(2006) Nat Genet 38 Suppl:S8-13.
[97]Rajewsky N. L(ou)sy miRNA targets? (2006) Nat Struct Mol Biol 13: 754 - 755
[98]Liu W, Mao SY, Zhu WY. Impact of tiny miRNAs on cancers.(2007) World J Gastroenterol 13(4):497-502.
[99]Melo CA, Melo SA. (2014). Biogenesis and Physiology of microRNAs. In M. Fabbri (Ed.), Non-coding RNAs and Cancer(Illustrated ed., p. 248 - 264). New york: Springer Science &{} Business Media, LLC 2014
[100]Gregory RI, Chendrimada TP, Shiekhattar R.MicroRNA biogenesis: isolation and characterization of the microprocessor complex.(2006) Methods Mol Biol 342:33-47.
[101]Bohnsack MT, Czaplinski K, Gorlich D.Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. (2004) RNA 10(2):185-91
[102]ENCODE Project Consortium, Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, et al. Identification and analysis of functional elements in 1\%{} of the human genome by the ENCODE pilot project. (2007) Nature 447(7146):799-816.
[103]Brosnan CA, Voinnet O. The long and the short of noncoding RNAs. (2009) Curr Opin Cell Biol 21(3):416-25. doi: 10.1016/j.ceb.2009.04.001.
[104]Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. (2009). Nature 458: 223-227 doi:10.1038/nature07672
[105]Pang KC, Frith MC, Mattick JS. Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function.(2006) Trends Genet 22(1):1-5
[106]Chen LL, Carmichael GG. Decoding the function of nuclear long non-coding RNAs.(2010) Curr Opin Cell Biol 22(3):357-64. doi: 10.1016/j.ceb.2010.03.003.
[107]Ponting CP, Oliver PL, Reik W. Evolution and Functions of Long Noncoding RNAs. (2009). Cell 136(4): 629 - 641
[108]Wang X, Arai S, Song X, Reichart D, Du K, Pascual G, et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. (2008). Nature 454(7200):126-30. doi: 10.1038/nature06992
[109]Lin D, Pestova TV, Hellen CU, Tiedge H. Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism. (2008). Mol Cell Biol 28(9):3008-19. doi: 10.1128/MCB.01800-07.
[110]Young TL, Matsuda T, Cepko CL. The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina. (2005) Curr Biol 15(6):501-12.
[111]Wang KC, Chang HY. Molecular Mechanisms of Long Noncoding RNAs. (2011). Mol Cell 43(6): 904 - 914
[112]Mourtada-Maarabouni M, Hedge VL, Kirkham L, Farzaneh F, Williams GT. Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5). (2008). J Cell Sci 121(Pt 7):939-46. doi: 10.1242/jcs.024646.
[113]Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. (2009) Nat Rev Genet 10(3):155-9. doi: 10.1038/nrg2521.
[114]Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. (2009) Proc Natl Acad Sci U S A.106(28):11667-72. doi: 10.1073/pnas.0904715106.
[115]Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, et al.Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. (2008). Mol Cell 32(2):232-46. doi: 10.1016/j.molcel.2008.08.022.
[116]Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. (2010). Nature 464:1071-1076 doi:10.1038/nature08975
[117]Fabbri M, Croce CM, Calin GA. MicroRNAs.(2008) Cancer J.14(1):1-6. doi: 10.1097/PPO.0b013e318164145e.
[118]PrensnerJR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. (2011). Nat Biotechnol 29: 742–749 doi:10.1038/nbt.1914
[119]Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. (2009). Genome Res.19: 92–105
[120]Calin GA, Croce CM. MicroRNA signatures in human cancers. (2006). Nat. Rev. Cancer. 6: 857–866
[121]Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. (2002). Proc Natl Acad Sci USA. 99: 15524–15529
[122]Chang S, Wang RH, Akagi K, Kim KA, Martin BK, Cavallone L, et al. Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155. (2011). Nat Med. 17(10):1275-82. doi: 10.1038/nm.2459.
[123]Chiosea S, Jelezcova E, Chandran U, Luo J, Mantha G, Sobol RW, Dacic S. Overexpression of dicer in precursor lesions of lung adenocarcinoma. (2007). Cancer Res. 67: 2345–2350
[124]Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. (2007). Nat. Genet. 39: 673–677
[125]Melo SA, Moutinho C, Ropero S, Calin GA, Rossi S, Spizzo R, et al. A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. (2010). Cancer Cell. 18: 303–315
[126]Chu H, Wang M, Shi D, Ma L, Zhang Z, Tong N, et al. Hsa-miR-196a2 Rs11614913 polymorphism contributes to cancer susceptibility: evidence from 15 case-control studies. (2011). PLoS. One. 6: e18108
[127]Paranjape T, Heneghan H, Lindner R, Keane FK, Hoffman A, Hollestelle A, et al. A 3’-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis. (2011). Lancet Oncol. 12: 377–386
[128]Humphreys KJ, Conlon MA, Young GP, Topping DL, Hu Y, Winter JM, et al. Dietary manipulation of oncogenic microRNA expression in human rectal mucosa: a randomized trial. (2014). Cancer Prev Res (Phila). 7(8):786-95. doi: 10.1158/1940-6207.CAPR-14-0053.
[129]Izzotti A, Larghero P, Longobardi M, Cartiglia C, Camoirano A, Steele VE, De Flora S. Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung. (2011). Mutat Res. 717(1-2):9-16. doi: 10.1016/j.mrfmmm.2010.12.008.
[130]Budhu A, Ji J, Wang XW. The Clinical Potential of microRNAs (2010). J. Hemato.l Oncol. 3:37
[131]Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C, et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. (2007). Cancer Cell. 12: 215–229
[132]Perez DS, Hoage TR, Pritchett JR, Ducharme-Smith AL, Halling ML, Ganapathiraju SC, et al. Long, abundantly expressed non-coding transcripts are altered in cancer. (2008). Hum Mol Genet. 17:642–55. http://dx.doi.org/10.1093/hmg/ddm336
[133]Silva JM, Perez DS, Pritchett JR, Halling ML, Tang H, Smith DI. Identification of long stress-induced non-coding transcripts that have altered expression in cancer. (2010). Genomics. 95:355–62. http://dx.doi.org/10.1016/j.ygeno.2010.02.009
[134]Redvers RP, Anderson RL. Long Non-Coding RNA: Agent Provocateur in Breast Cancer Metastasis. In R. Jandial (Ed.), Metastatic Cancer: Clinical and Biological Perspectives. Austin, Texas: Landes Bioscience 2000.
[135]Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, et al. MicroRNA-155 functions as an oncomir in breast cancer by targeting the suppressor of cytokine signaling 1 gene. (2010). Cancer Res 70: 3119–3127.
[136]Ovcharenko D, Kelnar K, Johnson C, Leng N, Brown D. Genome-scale microRNA and small interfering RNA screens identify small RNA modulators of trail-induced apoptosis pathway. (2007). Cancer Res 67: 10782–10788
[137]Di Leva G, Gasparini P, Piovan C, Ngankeu A, Garofalo M, Taccioli C, et al. MicroRNA cluster 221–222 and estrogen receptor alpha interactions in breast cancer. (2010). J. Natl. Cancer Inst 102: 706–721.
[138]Hu X, Guo J, Zheng L, Li C, Zheng TM, Tanyi JL, et al. The heterochronic microRNA let-7 inhibits cell motility by regulating the genes in the actin cytoskeleton pathway in breast cancer. (2013). Mol. Cancer Res 11: 240–250.
[139]He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, et al. A microRNA component of the p53 tumour suppressor network. (2007). Nature 447: 1130–1134.
[140]Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Korner H, et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. (2008). Cell Cycle 7: 2591–2600.
[141]Garofalo M, Jeon YJ, Nuovo GJ, Middleton J, Secchiero P, Joshi P, et al. Mir-34a/c-dependent pdgfr-alpha/beta downregulation inhibits tumorigenesis and enhances trail-induced apoptosis in lung cancer. (2013). PLoS One 8, e67581.
[142]Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. (2005). Cancer Res 65: 7065 – 7070.
[143]Chang YY, Kuo WH, Hung JH, Lee CY, Lee YH, Chang YC, et al. Deregulated microRNAs in triple negative breast cancer revealed by deep sequencing. (2015). Mol Cancer 14:36
[144]Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.(2010). Nature.464:1071–6.
[145]Chen W, Böcker W, Brosius J, Tiedge H. Expression of neural BC200 RNA in human tumours. (1997). J Pathol. 183:345–51.
[146]Iacoangeli A, Lin Y, Morley EJ, Muslimov IA, Bianchi R, Reilly J, et al. BC200 RNA in invasive and preinvasive breast cancer. (2004). Carcinogenesis.25:2125–33. http://dx.doi. org/10.1093/carcin/bgh228
[147]Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. (2007). Cell.129:131123. http://dx.doi.org/10.1016/j.cell.2007.05.022
[148]Wang H, Iacoangeli A, Popp S, Muslimov IA, Imataka H, Sonenberg N, et al. Dendritic BC1 RNA: functional role in regulation of translation initiation. (2002). J Neurosci.22:10232–41.
[149]Guffanti A, Iacono M, Pelucchi P, Kim N, Soldà G, Croft LJ, et al. A transcriptional sketch of a primary human breast cancer by 454 deep sequencing. (2009). BMC Genomics.10:163. http://dx.doi.org/10.1186/1471-2164-10-163
[150]Bamodu OA, Huang WC, Tzeng DT, Wu A, Wang LS, Chao TY, Yeh CT. Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of hsa-miR-448. (2015). BMC Cancer
[151]Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP. Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. (2010). Sci Signal. 3(107):ra8. doi: 10.1126/scisignal.2000568.
[152]Pickard MR, Williams GT. Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: implications for chemotherapy. (2014). Breast Cancer Res Treat. 145(2):359-70. doi: 10.1007/s10549-014-2974-y
[153]Luger K, Rechsteiner TJ, Flaus AJ, Waye MM, Richmond TJ. Characterization of nucleosome core particles containing histone proteins made in bacteria. (1997). JMol Biol 272(3):301–11.
[154]Campos EI, Reinberg D. Histones: annotating chromatin. (2009). Annu Rev Genet 43:559–99.
[155]Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 A resolution. (1997). Nature 389: 251–260.
[156]Robinson PJ, An W, Routh A, Martino F, Chapman L, Roeder RG, Rhodes D. 30 nm chromatin fibre decompaction requires both H4-K16 acetylation and linker histone eviction. (2008). J Mol Biol 381(4):816–25.
[157]Strahl BD, Allis CD. The language of covalent histone modifications. (2000). Nature 403: 41–45.
[158]Sanchez R, Zhou MM. The role of human bromodomains in chromatin biology and gene transcription. (2009). Curr Opin Drug Discov Develop 12(5): 659–65.
[159]Adams-Cioaba MA, Min J. Structure and function of histone methylation binding proteins. (2009). Biochem Cell Biol 87 (1): 93–105.
[160]Tropberger P, Schneider R. Going global: novel histone modifications in the globular domain of H3. (2010). Epigenetics 5 (2):112 – 117.
[161]Cosgrove MS, Boeke JD, Wolberger C. Regulated nucleosome mobility and the histone code. (2004). Nat Struct Mol Biol 11 (11):1037 – 1043.
[162]Cohen I, Poreba E, Kamieniarz K, Schneider R. Histone modifiers in cancer: friends or foes? (2011). Genes Cancer. 2:631–647
[163]Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. (2011). Cell Res. 21:381–395.
[164]Kouzarides T. Chromatin modifications and their function. (2007). Cell. 128:693–705.
[165]Khorasanizadeh S. The nucleosome: from genomic organization to genomic regulation.(2004). Cell.116 (2): 259 - 272.
[166]Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. (2007). Hum Mol Genet.16 (Spec1):R50–R59.
[167]Fullgrabe J, Kavanagh E, Joseph B. Histone onco-modifications. (2011). Oncogene 30: 3391 – 3403; doi:10.1038/onc.2011.121
[168]Kanwal R, Gupta S. Epigenetic modifications in cancer. (2012). Clin Genet 81(4): 303 – 311. doi:10.1111/j.1399-0004.2011.01809.x
[169]Robertson KD. DNA methylation and human disease. (2005). Nat Rev Genet. 6:597–610.
[170]Lin HJL, Zuo T, Chao JR, et al. Seed in soil, with an epigenetic view. (2009). Biochem Biophys Acta. 1790: 920–924.
[171]Baylin SB, Ohm JE. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? (2006). Nat Rev Cancer. 6(2):107-16.
[172]Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA, Collins HM, et al. Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome.(2009). Cancer Res. 69(9):3802-9.
[173]Branham MT, Marzese DM, Laurito SR, Gago FE, Orozco JI, Tello OM ,et al. Methylation profile of triple-negative breast carcinomas.(2012). Oncogenesis 1(7): e17. doi:10.1038/oncsis.2012.17
[174]Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86. doi: 10.1002/ijc.29210.
[175]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin.2011;61(2):69–90. doi: 10.3322/caac.20107.
[176]Berrada N, Delaloge S, André F. Treatment of triple-negative metastatic breast cancer: toward individualized targeted treatments or chemosensitization? Ann Oncol. 2010;21(suppl 7):vii30–5.
[177]Olopade OI, Grushko TA, Nanda R, Huo D. Advances in breast cancer: pathways to personalized medicine. Clin Cancer Res. 2008;14(24):7988–99. doi: 10.1158/1078-0432.CCR-08-1211.
[178]Turner N, Lambros MB, Horlings HM, Pearson A, Sharpe R, Natrajan R, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets.Oncogene. 2010;29(14):2013–23. doi: 10.1038/onc.2009.489.
[179]Schneider BP, Winer EP, Foulkes WD, Garber J, Perou CM, Richardson A, et al. Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res. 2008;14(24):8010–8. doi: 10.1158/1078-0432.CCR-08-1208.
[180]Gibb E, Brown C, Lam W. The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011;10(1):38. doi: 10.1186/1476-4598-10-38.
[181]Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, et al. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature. 2002;420(6915):563–73. doi: 10.1038/nature01266.
[182]Huttenhofer A, Schattner P, Polacek N. Non-coding RNAs: hope or hype? Trends Genet.2005;21(5):289–97. doi: 10.1016/j.tig.2005.03.007.
[183]Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, et al. The transcriptional landscape of the mammalian genome. Science. 2005;309(5740):1559–63. doi: 10.1126/science.1112014.
[184]Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013;73(3):1180–9. doi: 10.1158/0008-5472.CAN-12-2850.
[185]Li L, Feng T, Lian Y, Zhang G, Garen A, Song X. Role of human noncoding RNAs in the control of tumorigenesis. Proc Natl Acad Sci. 2009;106(31):12956–61. doi: 10.1073/pnas.0906005106.
[186]Wang Z, Tang F, Qi G, Yuan S, Zhang G, Tang B, et al. KDM5B is overexpressed in gastric cancer and is required for gastric cancer cell proliferation and metastasis. Am J Cancer Res. 2015;5(1):87–100.
[187]Dai B, Hu Z, Huang H, Zhu G, Xiao Z, Wan W, et al. Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21. Biochem Biophys Res Commun. 2014;454(1):221–7. doi: 10.1016/j.bbrc.2014.10.078.
[188]T argetScan. http://www.targetscan.org/ Accessed 12 February 2014.
[189]PicTar. http://pictar.mdc-berlin.de/ Accessed 12 February 2014.
[190]miRANDA. http://www.microrna.org/microrna/home.do Accessed 12 February 2014.
[191]The M-FOLD program. http://mfold.rna.albany.edu/?q=mfold Accessed 12 February 2014.
[192]Bellucci M, Agostini F, Masin M, Tartaglia GG. Predicting protein associations with long noncoding RNAs. Nat Methods. 2011;8(6):444–5. doi: 10.1038/nmeth.1611.
[193]The Cancer Genome Atlas (TCGA). https://tcga-data.nci.nih.gov/tcga Accessed 12 February 2014.
[194]The UCSC Cancer Browser. https://genome-cancer.ucsc.edu Accessed 12 February 2014.
[195]Oncomine. https://www.oncomine.org/resource/ Accessed 12 February 2014.
[196]The Gene Expression Omnibus (GEO). http://www.ncbi.nlm.nih.gov/geo Accessed 12 February 2014.
[197]Muppirala U, Honavar V, Dobbs D. Predicting RNA-protein interactions using only sequence information. BMC Bioinformatics. 2011;12(1):489. doi: 10.1186/1471-2105-12-489.
[198]Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010;466(7308):835–40. doi: 10.1038/nature09267.
[199]Zuker M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res.2003;31(13):3406–15. doi: 10.1093/nar/gkg595.
[200]GUI PyMOL software. http://pymol.org Accessed 18 May 2014.
[201]CatRAPID software. http://big.crg.cat/gene_function_and_evolution/services/catrapid Accessed 18 May 2014.
[202]Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123(3):725–31. doi: 10.1007/s10549-009-0674-9.
[203]Paolicchi E, Crea F, Farrar WL, Green JE, Danesi R. Histone lysine demethylases inbreast cancer. Crit Rev Oncol Hematol. 2013;86(2):97–103. doi: 10.1016/j.critrevonc.2012.11.008.
[204]Huang Y, Vasilatos SN, Boric L, Shaw PG, Davidson NE. Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Res Treat. 2012;131(3):777–89. doi: 10.1007/s10549-011-1480-8.
[205]Rotili D, Mai A. Targeting histone demethylases: a new avenue for the fight against cancer. Genes Cancer. 2011;2(6):663–79. doi: 10.1177/1947601911417976.
[206]Christensen J, Agger K, Cloos PA, Pasini D, Rose S, Sennels L, et al. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell. 2007;128(6):1063–76. doi: 10.1016/j.cell.2007.02.003.
[207]Scibetta AG, Santangelo S, Coleman J, Hall D, Chaplin T, Copier J, et al. Functional analysis of the transcription repressor PLU-1/JARID1B. Mol Cell Biol. 2007;27(20):7220–35. doi: 10.1128/MCB.00274-07.
[208]Xiang Y, Zhu Z, Han G, Ye X, Xu B, Peng Z, et al. JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer. Proc Natl Acad Sci U S A. 2007;104(49):19226–31. doi: 10.1073/pnas.0700735104.
[209]Yamane K, Tateishi K, Klose RJ, Fang J, Fabrizio LA, Erdjument-Bromage H, et al. PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Mol Cell.2007;25(6):801–12. doi: 10.1016/j.molcel.2007.03.001.
[210]Barrett A, Madsen B, Copier J, Lu PJ, Cooper L, Scibetta AG, et al. PLU-1 nuclear protein, which is upregulated in breast cancer, shows restricted expression in normal human adult tissues: a new cancer/testis antigen? Int J Cancer. 2002;101(6):581–8. doi: 10.1002/ijc.10644.
[211]Cho HS, Toyokawa G, Daigo Y, Hayami S, Masuda K, Ikawa N, et al. The JmjC domain-containing histone demethylase KDM3A is a positive regulator of the G1/S transition in cancer cells via transcriptional regulation of the HOXA1 gene. Int J Cancer. 2012;131(3):E179–89. doi: 10.1002/ijc.26501.
[212]Hayami S, Yoshimatsu M, Veerakumarasivam A, Unoki M, Iwai Y, Tsunoda T, et al. Overexpression of the JmjC histone demethylase KDM5B in human carcinogenesis: involvement in the proliferation of cancer cells through the E2F/RB pathway. Mol Cancer. 2010;9(1):59. doi: 10.1186/1476-4598-9-59.
[213]McMullin R, Wittner B, Yang C, Denton-Schneider B, Hicks D, Singavarapu R, et al. A BRCA1 deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly (ADP-ribose) polymerase inhibitor sensitivity. Breast Cancer Res. 2014;16(2):R25. doi: 10.1186/bcr3625.
[214]Rytelewski M, Tong JG, Buensuceso A, Leong HS, Maleki Vareki S, Figueredo R, et al. BRCA2 inhibition enhances cisplatin-mediated alterations in tumor cell proliferation, metabolism, and metastasis. Mol Oncol. 2014;8(8):1429–40. doi: 10.1016/j.molonc.2014.05.017.
[215]Carper MB, Denvir J, Boskovic G, Primerano DA, Claudio PP. RGS16, a novel p53 and pRb cross-talk candidate inhibits migration and invasion of pancreatic cancer cells. Genes Cancer. 2014;5(11–12):420–35.
[216]Chiu W-T, Lee H-T, Huang S, Aldape KD, Yao J, Steeg PS, et al. Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by Stat3 inhibition. Cancer Res. 2011.
[217]Liu XH, Lu KH, Wang KM, Sun M, Zhang EB, Yang JS, et al. MicroRNA-196a promotes non-small cell lung cancer cell proliferation and invasion through targeting HOXA5. BMC Cancer. 2012;12(1):348. doi: 10.1186/1471-2407-12-348.
[218]Kanematsu S, Yoshizawa K, Uehara N, Miki H, Sasaki T, Kuro M, et al. Sulforaphane inhibits the growth of KPL-1 human breast cancer cells in vitro and suppresses the growth and metastasis of orthotopically transplanted KPL-1 cells in female athymic mice. Oncol Rep. 2011;26(3):603–8.
[219]Kantara C, O’Connell MR, Luthra G, Gajjar A, Sarkar S, Ullrich RL, et al. Methods for detecting circulating cancer stem cells (CCSCs) as a novel approach for diagnosis of colon cancer relapse/metastasis.Lab Invest. 2015;95(1):100–12. doi: 10.1038/labinvest.2014.133.
[220]Kleffel S, Schatton T. Tumor dormancy and cancer stem cells: two sides of the same coin? Adv Exp Med Biol. 2013;734:145–79. doi: 10.1007/978-1-4614-1445-2_8.
[221]Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006;441(7091):349–53. doi: 10.1038/nature04733.
[222]Dey BK, Stalker L, Schnerch A, Bhatia M, Taylor-Papidimitriou J, Wynder C. The histone demethylase KDM5b/JARID1b plays a role in cell fate decisions by blocking terminal differentiation. Mol Cell Biol.2008;28(17):5312–27. doi: 10.1128/MCB.00128-08.
[223]Jiao F, Hu H, Yuan C, Wang L, Jiang W, Jin Z, et al. Elevated expression level of long noncoding RNA MALAT-1 facilitates cell growth, migration and invasion in pancreatic cancer. Oncol Rep. 2014;32(6):2485–92.
[224]Ying L, Chen Q, Wang Y, Zhou Z, Huang Y, Qiu F. Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition. Mol BioSyst. 2012;8(9):2289–94. doi: 10.1039/c2mb25070e.
[225]Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N. Triple-negative breast cancer—current status and future directions. Ann Oncol. 2009;20(12):1913–27. doi: 10.1093/annonc/mdp492.
[226]Price C, Chen J. MicroRNAs in cancer biology and therapy: current status and perspectives. Genes Dis.2014;1(1):53–63. doi: 10.1016/j.gendis.2014.06.004.
[227]Mulrane L, McGee SF, Gallagher WM, O’Connor DP. miRNA dysregulation in breast cancer. Cancer Res. 2013;73(22):6554–62. doi: 10.1158/0008-5472.CAN-13-1841.
[228]Braun JE, Huntzinger E, Fauser M, Izaurralde E. GW182 proteins directly recruit cytoplasmic deadenylase complexes to miRNA targets. Mol Cell. 2011;44(1):120–33. doi: 10.1016/j.molcel.2011.09.007.
[229]Chen CY, Shyu AB. Mechanisms of deadenylation-dependent decay. Wiley Interdiscip Rev RNA.2011;2(2):167–83. doi: 10.1002/wrna.40.
[230]Jinek M, Doudna JA. A three-dimensional view of the molecular machinery of RNA interference.Nature. 2009;457(7228):405–12. doi: 10.1038/nature07755.
[231]Rothschild S. microRNA therapies in cancer. Mol Cell Ther. 2014;2(1):7. doi: 10.1186/2052-8426-2-7.
[232]Cho HS, Park JH, Kim YJ. (2007). Epigenomics: novel aspect of genomic regulation. J Biochem Mol Biol. 40(2):151-5.

[233]Shukla S, Meeran SM, Katiyar SK. (2014). Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention. Cancer Lett. 355(1):9-17. doi: 10.1016/j.canlet.2014.09.017.
[234]Shankar E, Kanwal R, Candamo M, Gupta S. (2016). Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. Semin Cancer Biol. pii: S1044-579X(16)30011-6. doi: 10.1016/j.semcancer.2016.04.002
[235]Khan S, Shukla S, Sinha S, Meeran SM. (2016). Epigenetic targets in cancer and aging: dietary and therapeutic interventions. Expert Opin Ther Targets 20(6):689-703. doi: 10.1517/14728222.2016.1132702
[236]Thakur VS, Deb G, Babcook MA, Gupta S. (2014). Plant phytochemicals as epigenetic modulators: role in cancer chemoprevention. AAPS J. 16(1):151-63. doi: 10.1208/s12248-013-9548-5.
[237]Bamodu OA, Huang WC, Tzeng DT, Wu A, Wang LS, Yeh CT, Chao TY. (2015). Ovatodiolide sensitizes aggressive breast cancer cells to doxorubicin, eliminates their cancer stem cell-like phenotype, and reduces doxorubicin-associated toxicity. Cancer Lett. 364(2):125-34. doi: 10.1016/j.canlet.2015.05.006.
[238]Sayegh J, Cao J, Zou MR, Morales A, Blair LP, Norcia M, et al. (2013). Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen. J Biol Chem. 288(13):9408-17. doi: 10.1074/jbc.M112.419861.
[239]Hou YY, Wu ML, Hwang YC, Chang FR, Wu YC, Wu CC. (2009). The natural diterpenoid ovatodiolide induces cell cycle arrest and apoptosis in human oral squamous cell carcinoma Ca9-22 cells. Life Sci. 85(1-2):26-32. doi: 10.1016/j.lfs.2009.04.013.
[240]Rao YK, Chen YC, Fang SH, Lai CH, Geethangili M, Lee CC, Tzeng YM. (2013). Ovatodiolide inhibits the maturation of allergen-induced bone marrow-derived dendritic cells and induction of Th2 cell differentiation. Int Immunopharmacol. 17(3):617-24. doi: 10.1016/j.intimp.2013.08.002.
[241]Ho JY, Hsu RJ, Wu CL, Chang WL, Cha TL, Yu DS, Yu CP. (2013). Ovatodiolide Targets β -Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma. Evid Based Complement Alternat Med. 2013:161628. doi: 10.1155/2013/161628.
[242]J. Ferlay, H.R. Shin, F. Bray, D. Forman, C. Mathers, D.M. Parkin, GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer. <http://globocan.iarc.fr>, 2010.
[243]A. Jemal, F. Bray, M.M. Center, J. Ferlay, E. Ward, D. Forman, Global cancer statistics, CA Cancer J. Clin. 61 (2) (2011) 69–90.
[244]C. Carvalho, R.X. Santos, S. Cardoso, S. Correia, P.J. Oliveira, M.S. Santos, et al., Doxorubicin: the good, the bad and the ugly effect, Curr. Med. Chem. 16 (25) (2009) 3267–3285.
[245] T. Simunek, M. Sterba, O. Popelova, M. Adamcova, R. Hrdina, V. Gersl, Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron, Pharmacol. Rep. 61 (2009) 154–171.
[246] C.F. Thorn, C. Oshiro, S. Marsh, T. Hernandez-Boussard, H. McLeod, T.E. Klein, et al., Doxorubicin pathways: pharmacodynamics and adverse effects, Pharmacogenet. Genomics 21 (7) (2011) 440–446.
[247] F. Arcamone, G. Cassinelli, G. Fantini, A. Grein, P. Orezzi, C. Pol, et al., Adriamycin, 14-hydroxydaunomycin: a new antitumor antibiotic from S. peucetius var. caesius, Biotechnol. Bioeng. 11 (1969) 1101–1110.
[248]H. Cortes-Funes, C. Coronado, Role of anthracyclines in the era of targeted therapy, Cardiovasc. Toxicol. 7 (2007) 56–60.
[249]X. Zhao, J. Zhang, N. Tong, X. Liao, E. Wang, Z. Li, et al., Berberine attenuates doxorubicin-induced cardiotoxicity in mice, J. Int. Med. Res. 39 (2011) 1720–1727.
[250]A.M. Osman, H.M. Bayoumi, S.E. Al-Harthi, Z.A. Damanhouri, M.F. Elshal, Modulation of doxorubicin cytotoxicity by resveratrol in human breast cancer cell line, Cancer Cell Int. 12 (2012) 47–54.
[251]M. Arisawa, M. Nimura, A. Ikeda, et al., Biologically active macrocyclic diterpenoids from Chinese drug ‘Fang Feng Cao’. I. Isolation and structure, Planta Med. 52 (1986) 38–41.
[252]M. Arisawa, M. Nimura, A. Fujita, N. Morita, S. Koshimura, Biologically active macrocyclic diterpenoids from Chinese drug ‘Fang Feng Cao’. II. Derivatives of ovatodiolides and their cytotoxicity, Planta Med. 52 (1986) 297–299.
[253]M.S. Alam, M.A. Quader, M.A. Rashid, HIV-inhibitory diterpenoid from Anisomeles indica, Fitoterapia 71 (2000) 574–576.
[254]M.G. Dharmasiri,W.D. Ratnasooriya, M.I. Thabrew, Anti-inflammatory activity of decoctions of leaves and stems of Anisomeles indica at preflowering and flowering stages, Pharm. Biol. 40 (6) (2002) 433–439.
[255]Y.K. Rao, S.H. Fang, S.C. Hsieh, T.H. Yeh, Y.M. Tzeng, The constituents of Anisomeles indica and their anti-inflammatory activities, J. Ethnopharmocol. 121 (2) (2009) 292–296.
[256]M.G. Dharmasiri,W.D. Ratnasooriya, M.I. Thabrew,Water extract of leaves and stems of the preflowering but not flowering plants of Anisomeles indica possesses analgesic and antihyperalgesic activities in rats, Pharm. Biol. 41 (1) (2003) 37–44.
[257]Y.C.Wang, T.L. Huang, Screening of anti-Helicobacter pylori herbs deriving fromTaiwanese folk medicinal plants, FEMS Immunol.Med.Microbiol. 43 (2) (2005) 295–300.
[258]T.C. Huang, C.F. Hsieh, D.E. Boufford, C.S. Kuoh, H. Ohashi, C.I. Peng, et al., Flora of Taiwan, National Science Council of the Republic of China, Taiwan, 2003.
[259]Y. Momose, M. Nimura, M. Arisawa, T. Hayashi, R. Takeda, S. Nakanishi, Hypotensive activity of ovatodiolides isolated from a Chinese crude drug “Fang Feng Cao”, Phytother. Res. 8 (8) (1994) 482–484.
[260]Y.Y. Hou, M.L. Wu, Y.C. Hwang, F.R. Chang, Y.C. Wu, C.C. Wu, The natural diterpenoid ovatodiolide induces cell cycle arrest and apoptosis in human oral squamous cell carcinoma Ca9-22 cell, Life Sci. 85 (2009) 26–32.
[261]K.L. Lin, P.C. Tsai, C.Y. Hsieh, L.S. Chang, S.R. Lin, Antimetastatic effect and mechanism of ovatodiolide in MDA-MB-231 human breast cancer cells, Chem. Biol. Interact. 194 (2011) 148–158.
[262]V. Vichai, K. Kirtikara, Sulforhodamine B colorimetric assay for cytotoxicity screening, Nat. Protoc. 1 (2006) 1112–1116.
[263]S. Kitagawa, T. Nabekura, S. Kamiyama, Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells, J. Pharm. Pharmacol. 56 (8) (2004) 1001–1005.
[264]S.N. Hilmer, V.C. Coqqer, M. Muller, D.G. Le Couter, The hepatic pharmacokinetics of doxorubicin and liposomal doxorubicin, Drug Metab. Dispos. 32 (2004) 794–799.
[265]T.A. Buchholz, D.N. Stivers, J. Stec, M. Ayers, E. Clark, A. Bolt, et al., Global gene expression changes during neoadjuvant chemotherapy for human breast cancer, Cancer J. 8 (2002) 461–468.
[266]O. Tacar, P. Sriamornsak, C.R. Dass, Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems, J. Pharm. Pharmacol. 65 (2013) 157–170.
[267]Y. Fernandez, L. Espana, S. Manas, A. Fabra, A. Sierra, Bcl-xL promotesmetastasis of breast cancer cells by induction of cytokines resistance, Cell Death Differ. 7 (2000) 350–359.
[268]R. Garcia, T.L. Bowman, G. Niu, H. Yu, S. Minton, C.A. Muro-Cacho, et al., Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells, Oncogene 20 (2001) 2499–2513.
[269]A. Sierra, J.E. Price, M. Garcia-Ramirez, O. Mendez, L. Lopez, A. Fabra, Astrocytederived cytokines contribute to the metastatic brain specificity of breast cancer cells, Lab. Invest. 77 (1997) 357–368.
[270] P.J. Real, A. Sierra, A. de Juan, J.C. Segovia, J.M. Lopez-Vega, J.L. Fernandez-Luna, Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells, Oncogene 21 (2002) 7611–7618.
[271]E.H. Yi, C.S. Lee, J.K. Lee, Y.J. Lee, M.K. Shin, C.H. Cho, et al., STAT3-RANTES autocrine signaling is essential for tamoxifen resistance in human breast cancer cells, Mol. Cancer Res. 11 (1) (2013) 31–42.
[272]L.L. Marotta, V. Almendro, A. Marusyk, M. Shipitsin, J. Schemme, S.R. Walker, et al., The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24−stem cell-like breast cancer cells in human tumors, J. Clin. Invest. 121 (7) (2011) 2723–2735.
[273] Z.C. Hartman, X.Y. Yang, O. Glass, G. Lei, T. Osada, S.S. Dave, et al., HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis, Cancer Res. 71 (2011) 4380–4391.
[274]Y.H. Ling, A.K. el-Naggar, W. Priebe, R. Perez-Soler, Cell cycle-dependent cytotoxicity, G2/M phase arrest, and disruption of p34cdc2/cyclin B1 activity induced by doxorubicin in synchronized P388 cells, Mol. Pharmacol. 49 (5) (1996) 832–841.
[275]L. Bao, A. Haque, K. Jackson, S. Hazari, K. Moroz, R. Jetly, et al., Increased expression of P-glycoprotein is associated with doxorubicin chemoresistance in the metastatic 4T1 breast cancer model, Am. J. Pathol. 178 (2) (2011) 838–852.
[276]L. Bao, S. Hazari, S. Mehra, D. Kaushal, K. Moroz, S. Dash, Increased expression of P-glycoprotein and doxorubicin chemoresistance of metastatic breast cancer is regulated by miR-298, Am. J. Pathol. 180 (6) (2011) 2490–2503.
[277]K.P. Patel, I.F. Tannock, The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors, BMC Cancer 9 (2009) 356–366.
[278]J.H. Lin, M. Yamazaki, Role of P-glycoprotein in pharmacokinetics: clinical implications, Clin. Pharmacokinet. 42 (1) (2003) 59–98.
[279]A.M. Gonzalez-Angulo, F. Morales-Vasquez, G.N. Hortobagyi, Overview of resistance to systemic therapy in patients with breast cancer, Adv. Exp. Med. Biol. 608 (2007) 1–22.
[280]Q.Q. Li, J.D. Xu, W.J. Wang, X.X. Cao, Q. Chen, F. Tang, et al., Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells, Clin. Cancer Res. 15 (8) (2009) 2657–2665.
[281] M. Maugeri-Saccà, P. Vigneri, R. De Maria, Cancer stem cells and chemosensitivity, Clin. Cancer Res. 17 (2011) 4942–4947.
[282]M. Maugeri-Saccà, A. Zeuner, R. De Maria, Therapeutic targeting of cancer stem cells, Front. Oncol. 1 (2011) 10, doi:10.3389/fonc.2011.00010.
[283]A.M. Calcagno, C.D. Salcido, J.P. Gillet, C.P. Wu, J.M. Fostel, M.D. Mumau, et al., Prolonged drug selection of breast cancer cells and enrichment of cancer stem cell characteristics, J. Natl. Cancer Inst. 102 (21) (2010) 1637–1652.
[284]H.E. Lee, J.H. Kim, Y.J. Kim, S.Y. Choi, S.W. Kim, E. Kang, et al., An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer, Br. J. Cancer 104 (2011) 1730–1738.