臺灣博碩士論文加值系統

台灣三陰性乳癌的患病率佔所有乳癌病人約為15％。在不同三陰性乳癌患者之間的基因變異甚大，而這樣的個體異質性總是讓臨床醫師在治療病患時，需要面對多種的挑戰；由於缺乏共同的標的，化學治療仍是三陰性乳癌患者的主要治療方法，而尋找初新的治療標的，是目前醫學上重要的工作。回顧過去，已有研究指出表皮生長因子受體（EGFR）約在70% 三陰性乳癌患者中有過度表現，象徵著較差的預後。不過，在臨床試驗單一使用EGFR單株抗體治療效果卻比單用化學治療差，反之EGFR單株抗體合併化學治療則效果最佳，這樣的結果暗示EGFR對腫瘤生長的影響，可能須合併其他的因子。同為跨膜蛋白的纖維細胞生長因子受體1（FGFR1）之過度表現，在最近的臨床研究中也有被提出為乳癌病人預後較差的預測因子。因此我們試圖去探討EGFR及FGFR1在台灣三陰性乳癌中的表現及其相互作用。
首先，我們利用單株抗體進行免疫組織化學染色，檢查台灣三陰性乳癌組織的特定蛋白質表現；進一步根據染色強度分類，分析相關的病人及腫瘤資料。我們發現EGFR的過度表現與病人之預後不佳，具有強烈關聯性；而FGFR1的表現與病人的預後無關。但在EGFR表現較低的族群，預後較差的族群反而有FGFR1的過度表現；因此我們推斷，EGFR與FGFR1兩者之間的關係，在乳癌生長的調節過程中，並非為共同合作（co-occurrence）。另外，利用基因共享資料庫PrognoScan及cBioPortal分析EGFR與FGFR1的信使核糖核酸 (mRNA) 量以及拷貝數變異 (copy number alteration) 之表現也呈現相同的趨勢。
根據我們的研究，EGFR的過度表現在台灣三陰性乳癌病人中的預後較差，而在EGFR表現較低的族群，FGFR1的過度表現代表著預後較差。由此推斷，FGFR1可能在EGFR沒有被活化的情況下參與三陰性乳癌的癌症調節途徑。

Prevalence of triple negative breast cancer (TNBC) is around 15% in Taiwan and the treatment presents a major clinical challenge owing to heterogeneity of cancer genome. Currently, chemotherapy is the mainstay of treatment of TNBC patients due to lack of common target. Searching new therapeutic target is an important issue for TNBC patients. In the previous studies, overexpression of epidermal growth factor receptor (EGFR) is detected in approximately 70% of TNBC populations and indicated as a negative prognostic factor. However, the response of single use of EGFR monoclonal antibody (Cetuximab) did not achieve a better outcome comparing to combination of cetuximab and cisplatin in phase II clinical trial. This result suggests that most patients have alternate mechanisms other than EGFR pathway. Overexpression of fibroblast growth factor receptor 1 (FGFR1), which is also a transmembrane protein, has also been proposed as a poor prognostic factor for breast cancer in recent clinical studies. Therefore, we tried to investigate the expression and interaction of EGFR and FGFR1 in triple negative breast cancer in Taiwan population.
First, we tested the immunohistochemical staining with monoclonal antibody to examine the expression of targeted protein in triple-negative breast cancer. We analyzed the clinicopathological and survival information based on the immunoscoring. There was strong correlation between the overexpression of EGFR and poor prognosis of the patients; however, the relationship between clinical prognosis of the patients and expression of FGFR1 was weak. After further analysis, FGFR1 overexpression was correlated with poor prognosis in low EGFR expression groups. We presumed that the relationship between the EGFR and FGFR1 in the regulation of tumor growth was not co-occurrence. In addition, analyzing the mRNA expression and copy number alteration (CNA) of these two genes also showed the same trend in the public database (PrognoScan ＆ cBioPortal)
According to our study, overexpression of EGFR was correlated to poor outcome in TNBC populations. In patients with low EGFR expression, FGFR1 overexpression predicted poor prognosis. FGFR1 might participate in the regulation pathway of TNBC in the absence of EGFR activation.

中文摘要 II
English Abstract III
ACKNOWLEDGEMENT V
TABLE OF CONTENTS VI
LIST OF FIGURES VIII
LIST OF TABLES X
ABBREVIATIONS XI
INTRODUCTION 1
TNBC: symbol of poor prognosis 1
Heterogeneity of TNBC 1
Role of EGFR in TNBC 2
Role of FGFR1 in TNBC 3
MATERIALS AND METHODS 7
1. Tissue microarray 7
2. Immunohistochemical staining 7
3. PrognoScan and cBioPortal analysis 9
4. Statistics analysis 9
RESULTS 11
1. Details of patient studies 11
2. Immunohistochemistry 12
3. Clinicopathological characteristics in different expression groups 13
4. Survival analysis 16
5. Relationship between EGFR and FGFR1 21
6. mRNA expression of EGFR and FGFR1 23
7. Gene amplification of EGFR and FGFR1 25
DISCUSSION 28
CONCLUSION 32
REFERENCES 33

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