title: FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis.
abstract: The association between breast cancer risk and genetic variants of fibroblast growth factor receptor 2 (FGFR2) has been identified and repeatedly confirmed; however, the mechanism underlying FGFR2 in breast tumorigenesis remains obscure. Given that breast tumorigenesis is particularly related to DNA double-strand-break-repair (DSBR), we examined the hypothesis that FGFR2 is involved in DSBR. Our results show that expression of Mre11, a vital exonuclease in DSBR, is downregulated by FGFR2, which is further linked to decreased DSBR. Analysis of the Mre11 promoter revealed that POU1F1 mediates FGFR2-induced Mre11 downregulation. Furthermore, ERK, downstream of FGFR2, directly interacts with and phosphorylates POU1F1, increasing POU1F1 binding capacity to the Mre11 promoter and repressing Mre11 expression, which consequently affects DSBR and sensitizes breast cancer cells to chemotherapeutic treatments. The importance of the FGFR2-Mre11-DSBR link in cancer progression is suggested by the finding that genotypes of FGFR2 and Mre11 are associated with survival of breast cancer patients and that FGFR2 expression correlates with cancer prognosis specifically in patients receiving chemotherapy. This study yields important insight into the role of FGFR2 in breast tumorigenesis and may facilitate development of a useful therapeutic approach for breast cancer.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan and.
authors: Yuan-Ling
authors: YL
authors: Huang
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan and.
authors: Wen-Cheng
authors: WC
authors: Chou
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan and.
authors: Chia-Ni
authors: CN
authors: Hsiung
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan and.
authors: Ling-Yueh
authors: LY
authors: Hu
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan and.
authors: Hou-Wei
authors: HW
authors: Chu
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan and College of Public Health, China Medical University, Taichong 404, Taiwan bmcys@ibms.sinica.edu.tw.
authors: Chen-Yang
authors: CY
authors: Shen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D004198:Disease Susceptibility; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D000076228:MRE11 Homologue Protein; D008954:Models, Biological; D010766:Phosphorylation; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D050817:Transcription Factor Pit-1 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C494187:POU1F1 protein, human; D050817:Transcription Factor Pit-1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D000076228:MRE11 Homologue Protein