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系統識別號 U0026-0808201921304600
論文名稱(中文) 分析FGFR1和EGFR在三陰性乳癌的表現及其交互作用
論文名稱(英文) Expression of FGFR1 and EFGR in triple negative breast cancer and analyzing their interaction
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所碩士在職專班
系所名稱(英) Institute of Clinical Medicine(on the job class)
學年度 107
學期 2
出版年 108
研究生(中文) 羅竹君
研究生(英文) Zhu-Jun Loh
學號 S97061085
學位類別 碩士
語文別 英文
論文頁數 35頁
口試委員 口試委員-陳芃潔
口試委員-鄭修琦
指導教授-徐慧萍
指導教授-呂佩融
中文關鍵字 三陰性乳癌  表皮生長因子受體  纖維細胞生長因子受體1  預後預測因子 
英文關鍵字 Triple negative breast cancer  Epidermal growth factor receptor  Fibroblast growth factor receptor 1  Prognostic predictors 
學科別分類
中文摘要 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。
英文摘要 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.
論文目次 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
參考文獻 1. Siddharth S, Sharma D. Racial Disparity and Triple-Negative Breast Cancer in African-American Women: A Multifaceted Affair between Obesity, Biology, and Socioeconomic Determinants. Cancers (Basel) 2018; 10(12).
2. Tseng LM, Chiu JH, Liu CY, et al. A comparison of the molecular subtypes of triple-negative breast cancer among non-Asian and Taiwanese women. Breast Cancer Res Treat 2017; 163(2): 241-54.
3. Lehmann BD, Jovanovic B, Chen X, et al. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One 2016; 11(6): e0157368.
4. Lehmann BD, Pietenpol JA. Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol 2014; 232(2): 142-50.
5. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011; 121(7): 2750-67.
6. Yam C, Mani SA, Moulder SL. Targeting the Molecular Subtypes of Triple Negative Breast Cancer: Understanding the Diversity to Progress the Field. The Oncologist 2017; 22(9): 1086-93.
7. Baselga J, Gomez P, Greil R, et al. Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol 2013; 31(20): 2586-92.
8. Sarabipour S. Parallels and Distinctions in FGFR, VEGFR, and EGFR Mechanisms of Transmembrane Signaling. Biochemistry 2017; 56(25): 3159-73.
9. Del Piccolo N, Sarabipour S, Hristova K. A New Method to Study Heterodimerization of Membrane Proteins and Its Application to Fibroblast Growth Factor Receptors. J Biol Chem 2017; 292(4): 1288-301.
10. Baek KH, Hong ME, Jung YY, et al. Correlation of AR, EGFR, and HER2 Expression Levels in Prostate Cancer: Immunohistochemical Analysis and Chromogenic In Situ Hybridization. Cancer Res Treat 2012; 44(1): 50-6.
11. Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell 2018; 173(2): 321-37 e10.
12. Gallo LH, Nelson KN, Meyer AN, Donoghue DJ. Functions of Fibroblast Growth Factor Receptors in cancer defined by novel translocations and mutations. Cytokine Growth Factor Rev 2015; 26(4): 425-49.
13. Wu J, Wang Y, Liu J, Chen Q, Pang D, Jiang Y. Effects of FGFR1 Gene Polymorphisms on the Risk of Breast Cancer and FGFR1 Protein Expression. Cell Physiol Biochem 2018; 47(6): 2569-78.
14. Wang W, Meng Y, Dong B, et al. A Versatile Tumor Gene Deletion System Reveals a Crucial Role for FGFR1 in Breast Cancer Metastasis. Neoplasia 2017; 19(5): 421-8.
15. Massabeau C, Sigal-Zafrani B, Belin L, et al. The fibroblast growth factor receptor 1 (FGFR1), a marker of response to chemoradiotherapy in breast cancer? Breast Cancer Res Treat 2012; 134(1): 259-66.
16. Kobayashi M, Huang Y, Jin C, et al. FGFR1 abrogates inhibitory effect of androgen receptor concurrent with induction of androgen-receptor variants in androgen receptor-negative prostate tumor epithelial cells. Prostate 2011; 71(15): 1691-700.
17. Tomiguchi M, Yamamoto Y, Yamamoto-Ibusuki M, et al. Fibroblast growth factor receptor-1 protein expression is associated with prognosis in estrogen receptor-positive/human epidermal growth factor receptor-2-negative primary breast cancer. Cancer Science 2016; 107(4): 491-8.
18. Turner N, Pearson A, Sharpe R, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 2010; 70(5): 2085-94.
19. Formisano L, Stauffer KM, Young CD, et al. Association of FGFR1 with ERalpha Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER(+) Breast Cancer. Clin Cancer Res 2017; 23(20): 6138-50.
20. Cheng CL, Thike AA, Tan SYJ, Chua PJ, Bay BH, Tan PH. Expression of FGFR1 is an independent prognostic factor in triple-negative breast cancer. Breast Cancer Research and Treatment 2015; 151(1): 99-111.
21. Chen Z, Tong L-j, Tang B-y, et al. C11, a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor, suppresses breast cancer metastasis and angiogenesis. Acta Pharmacologica Sinica 2018; 40(6): 823-32.
22. Sharpe R, Pearson A, Herrera-Abreu MT, et al. FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo. Clin Cancer Res 2011; 17(16): 5275-86.
23. Fedchenko N, Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue - a review. Diagn Pathol 2014; 9: 221.
24. Mizuno H, Kitada K, Nakai K, Sarai A. PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med Genomics 2009; 2: 18.
25. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013; 6(269): pl1.
26. Desmedt C, Piette F, Loi S, et al. Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res 2007; 13(11): 3207-14.
27. Sotiriou C, Wirapati P, Loi S, et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 2006; 98(4): 262-72.
28. Mina A, Yoder R, Sharma P. Targeting the androgen receptor in triple-negative breast cancer: current perspectives. OncoTargets and Therapy 2017; Volume 10: 4675-85.
29. Kalimutho M, Parsons K, Mittal D, Lopez JA, Srihari S, Khanna KK. Targeted Therapies for Triple-Negative Breast Cancer: Combating a Stubborn Disease. Trends Pharmacol Sci 2015; 36(12): 822-46.
30. Lerma E, Barnadas A, Prat J. Triple Negative Breast Carcinomas: Similarities and Differences With Basal Like Carcinomas. Applied Immunohistochemistry & Molecular Morphology 2009; 17(6): 483-94.
31. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 2012; 30(21): 2615-23.
32. Chavez KJ, Garimella SV, Lipkowitz S, Eng-Wong J, Zujewski JA. Triple negative breast cancer cell lines: One tool in the search for better treatment of triple negative breast cancer. Breast Disease 2011; 32(1-2): 35-48.
33. Costa R, Shah AN, Santa-Maria CA, et al. Targeting Epidermal Growth Factor Receptor in triple negative breast cancer: New discoveries and practical insights for drug development. Cancer Treat Rev 2017; 53: 111-9.
34. Chen S, Qiu Y, Guo P, Pu T, Feng Y, Bu H. FGFR1 and HER1 or HER2 co‑amplification in breast cancer indicate poor prognosis. Oncology Letters 2018.
35. Prat A, Adamo B, Cheang MC, Anders CK, Carey LA, Perou CM. Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist 2013; 18(2): 123-33.
36. Sobhani N, Ianza A, D'Angelo A, et al. Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer. Cells 2018; 7(7).
37. Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer 2017; 17(5): 318-32.
38. Reis-Filho JS, Simpson PT, Turner NC, et al. FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin Cancer Res 2006; 12(22): 6652-62.
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