Abstract 2156: FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Purpose: 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. Experimental design: This study started with the demonstration that FGFR2 impaired DSBR. Subsequent screening of the expression of genes functionally related to DSBR was performed and possible signaling pathways downstream of FGFR2 were examined. Data from independent breast cancer patient cohorts was used to confirm that difference in progression of patients can be explained by the findings identified in cell model. Results: 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. Conclusion: 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. With the move toward personalized therapy, which has gradually become a clinical reality, the findings of the present study suggest that FGFR2 expression may be a potential biomarker for selecting a suitable subgroup of breast cancer patients to receive chemotherapy or to determine the optimal chemotherapeutic dose. Citation Format: Yuan-Ling Huang, Wen-Cheng Chou, Chia-Ni Hsiung, Ling-Yueh Hu, Hou-Wei Chu, Chen-Yang Shen. FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2156. doi:10.1158/1538-7445.AM2015-2156