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

Human Molecular Genetics
Yuan-Ling HuangChen-Yang Shen

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 th...Continue Reading

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Citations

Mar 10, 2017·Scientific Reports·Wen-Cheng ChouChen-Yang Shen
Oct 28, 2018·Nature Reviews. Clinical Oncology·Masaru Katoh
Apr 23, 2016·Oncotarget·Puja GaurTej K Pandita
Dec 22, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Thomas ChabotFabrice Fleury

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