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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Abstract

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
Volume7
Issue number1
DOIs
Publication statusPublished - 14 Aug 2017

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Di Benedetto, A., Ercolani, C., Mottolese, M., Sperati, F., Pizzuti, L., Vici, P., Terrenato, I., Shaaban, A. M., Humphries, M. P., Di Lauro, L., Barba, M., Vitale, I., Ciliberto, G., Speirs, V., De Maria, R., & Maugeri-Saccà, M. (2017). Analysis of the ATR-Chk1 and ATM-Chk2 pathways in male breast cancer revealed the prognostic significance of ATR expression. Scientific Reports, 7(1), [8078]. https://doi.org/10.1038/s41598-017-07366-7