Analysis of the ATR-Chk1 and ATM-Chk2 pathways in male breast cancer revealed the prognostic significance of ATR expression

Anna Di Benedetto, Cristiana Ercolani, Marcella Mottolese, Francesca Sperati, Laura Pizzuti, Patrizia Vici, Irene Terrenato, Abeer M Shaaban, Matthew P Humphries, Luigi Di Lauro, Maddalena Barba, Ilio Vitale, Gennaro Ciliberto, Valerie Speirs, Ruggero De Maria, Marcello Maugeri-Saccà

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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. Herein we investigated the ATR-Chk1 and ATM-Chk2 signalings in male breast cancer (MBC). 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. Survival analyses were carried out in 112 patients. Survival curves were estimated with the Kaplan-Meier method and compared by log-rank test. Cox proportional regression models were generated to identify variables impacting survival outcomes. 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). 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). Overall, the ATR/ATM-initiated molecular cascade seems to be active in a fraction of MBC patients and may represent a negative prognostic factor.

Original languageEnglish
Article number8078
JournalScientific Reports
Issue number1
Publication statusPublished - 14 Aug 2017
Externally publishedYes

Bibliographical note

We thank members of the Male Breast Cancer Consortium for kindly contributing cases. We thank Tania Merlino for technical assistance. This study was supported by Breast Cancer Now (formerly Breast Cancer Campaign; grant 2007MayPR02 to V.S. and A.M.S.) and Yorkshire Cancer Research (grant L378 to V.S.).


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