As a result, most common tumors were stratified into a number of subtypes, each characterized by specific genomic alterations and deregulated pathways. Impressive advancements have been made in the molecular characterization of tumours over the last decade. The hormone-dependent nature of MBC is exploited for therapeutic purposes, since hormone therapies including tamoxifen 4, aromatase inhibitors 5, 6, 7, fulvestrant 8, GnRH analogues 9, and antiandrogens 10 have shown antitumor activity, albeit in retrospective studies. Indeed, MBC is a disease of elderly men, which frequently expresses steroid receptors, namely the estrogen receptor (ER), progesterone receptor (PgR) and androgen receptor (AR) 1, 3. Male breast cancer (MBC) is a rare neoplasm that shares similarities with post-menopausal breast cancer 1, 2. Overall, the ATR/ATM-initiated molecular cascade seems to be active in a fraction of MBC patients and may represent a negative prognostic factor. Multivariate Cox models of 10-year survival and overall indicated that pATR expression, alone or combined with pChk2, was an independent predictor of adverse outcomes (10-year survival: pATR: HR 2.74, 95% CI: 1.23–6.10 pATR/pChk2: HR 2.92, 95% CI: 1.35–6.33 overall survival: pATR: HR 2.58, 95% CI: 1.20–5.53 pATR/pChk2: HR 2.89, 95% CI: 1.37–6.12). The expression of pATR conferred poorer survival outcomes (log rank p = 0.013, p = 0.007 and p = 0.010 for overall, 15- and 10-year survival, respectively). Cox proportional regression models were generated to identify variables impacting survival outcomes. Survival curves were estimated with the Kaplan-Meier method and compared by log-rank test. Survival analyses were carried out in 112 patients. The expression of DDR kinases (pATR, pATM, pChk1, pChk2, and pWee1) and DNA damage markers (pRPA32 and γ-H2AX) was evaluated by immunohistochemistry in 289 MBC samples to assess their association. Herein we investigated the ATR-Chk1 and ATM-Chk2 signalings in male breast cancer (MBC). The ATR-Chk1 and ATM-Chk2 pathways are central in DNA damage repair (DDR) and their over-activation may confer aggressive molecular features, being an adaptive response to endogenous DNA damage and oncogene-induced replication stress.
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