臺灣博碩士論文加值系統

三陰性乳腺癌（triple negative breast cancer, TNBC）被認為對放射治
療不敏感，需要專門為 TNBC 開發放射增敏劑。在先前的研究中，
我們建立了一個來自 MDA-MB-231 細胞的抗放射細胞株，稱之為
231-RR，並且我們證明這些抗放射細胞表現出高癌幹細胞（Cancer
stem cells, CSCs）活性。在本研究中，我們發現 231-RR 細胞中 Src
激酶的磷酸化程度增加。使用 Dasatinib，一種 Src抑制劑，處理 231-
RR 細胞則使其提升對放射治療的敏感性，並導致 p-H2AXser139
(H2AX) 的增加，顯示抑制 Src 活性導致 TNBC 細胞中 DNA 損傷增
強。Dasatinib 還造成癌幹細胞因子的下調，包括 c-Myc、OCT4 和
Notch 細胞內區域蛋白(the intracellular domain of Notch)。此外，我們
觀察到訊號轉導和轉錄活化因子 3（the signal transducer and activator
of transcription 3, STAT3）的磷酸化減少；使用 C188-9，一種 STAT3
抑制劑，也使 231-RR 細胞對放射治療產生敏感性，並增加 H2AX
的表現，但 C188-9 處理並未改變 Src 的磷酸化，這顯示 STAT3 的活
化為 Src 的下游訊號分子。此外，我們觀察到在使用 Dasatinib 或
C188-9治療後，p-ATMser1981的表現量增加，而231-RR抗放射線細胞
對 ATM 抑制劑 AZD1390 則較原始 MDA-MB-231 細胞具更高的敏感
性，這表示 ATM 抑制劑可以與放射治療結合用於 TNBC 治療。總而
言之，我們的數據顯示針對 Src/STAT3/ATM 等分子的抑制劑具有成
為 TNBC 放射增敏劑的潛力，並可作為癌幹細胞的標靶治療藥物。

Triple-negative breast cancer (TNBC) is known to be insensitive to
radiotherapy, necessitating the development of radiosensitizers specifically
for TNBC. In a previous study, we established a radioresistant sub-line
derived from MDA-MB-231 cells, which we named 231-RR, and found
that these cells exhibited a high level of cancer stem cell (CSC) activity. In
the present study, we found that Src kinase activation was increased in 231-
RR cells. Treatment with dasatinib, a Src inhibitor, sensitized 231-RR cells
to radiotherapy and led to an increase in p-H2AXSer139 (H2AX), indicating
increased DNA damage. Dasatinib also downregulated cancer stemness
factors, including c-Myc, OCT4 and the intracellular domain of Notch. In
addition, we observed a decrease in the phosphorylation of the signal
transducer and activator of transcription 3 (STAT3) upon dasatinb
treatment in 231-RR cells. Treatment with C188-9, a STAT3 inhibitor, also
sensitized 231-RR cells to radiotherapy and increased H2AX levels, but
did not alter Src phosphorylation. This suggests that STAT3 activation is a
downstream event following Src activation. We also observed an increase
in p-ATMser1981 levels following treatment with either dasatinib or C188-9
in 231-RR cells. These radioresistant cells also showed increased
sensitivity to AZD1390, an ATM inhibitor, compared to the parental MDAMB-231 cells, suggesting that ATM inhibitors could be used in
combination with radiotherapy for the treatment of TNBC. In conclusion,
our data suggest that inhibitors targeting Src, STAT3 or ATM could act as
radiosensitizers or CSC-targeting agents in TNBC radiotherapy.

中文摘要.......................................................................I
Abstract.....................................................................III
緒論...........................................................................1
三陰性乳癌 (Triple Negative Breast Cancer).....................................1
放射治療 (Radiation Therapy) ..................................................2
c-Src & Dasatinib .............................................................3
STAT3 & C188-9.................................................................5
ATM & AZD1390..................................................................6
癌幹細胞 (Cancer stem cells, CSCs).............................................8
研究動機......................................................................10
實驗方法......................................................................11
1. 細胞培養...................................................................11
2. 蛋白質濃度測定與定量........................................................13
3. 西方墨點法(Western Blot)...................................................14
4. MTT 試驗...................................................................16
5. Clonogenic assay...........................................................17
6. 免疫螢光染色(Immunofluorescence, IF)........................................18
研究材料與設備 ................................................................19
實驗材料......................................................................19
抗體..........................................................................22
抑制劑........................................................................23
耗材..........................................................................23
器材..........................................................................23
結果..........................................................................25
討論.............................. ...........................................30
結果圖........................................................................37
參考文獻......................................................................51

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