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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Male Breast Neoplasms
Survival
DNA Damage
DNA Repair
Survival Analysis
Genetic Markers
Oncogenes
Proportional Hazards Models
Phosphotransferases
Immunohistochemistry

Keywords

  • Journal Article

Cite this

Di Benedetto, A., Ercolani, C., Mottolese, M., Sperati, F., Pizzuti, L., Vici, P., ... 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

Analysis of the ATR-Chk1 and ATM-Chk2 pathways in male breast cancer revealed the prognostic significance of ATR expression. / Di Benedetto, Anna; Ercolani, Cristiana; Mottolese, Marcella; Sperati, Francesca; Pizzuti, Laura; Vici, Patrizia; Terrenato, Irene; Shaaban, Abeer M; Humphries, Matthew P; Di Lauro, Luigi; Barba, Maddalena; Vitale, Ilio; Ciliberto, Gennaro; Speirs, Valerie; De Maria, Ruggero; Maugeri-Saccà, Marcello.

In: Scientific Reports, Vol. 7, No. 1, 8078, 14.08.2017.

Research output: Contribution to journalArticle

Di Benedetto, A, Ercolani, C, Mottolese, M, Sperati, F, Pizzuti, L, Vici, P, Terrenato, I, Shaaban, AM, Humphries, MP, 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, vol. 7, no. 1, 8078. https://doi.org/10.1038/s41598-017-07366-7
Di Benedetto, Anna ; Ercolani, Cristiana ; Mottolese, Marcella ; Sperati, Francesca ; Pizzuti, Laura ; Vici, Patrizia ; Terrenato, Irene ; Shaaban, Abeer M ; Humphries, Matthew P ; Di Lauro, Luigi ; Barba, Maddalena ; Vitale, Ilio ; Ciliberto, Gennaro ; Speirs, Valerie ; De Maria, Ruggero ; Maugeri-Saccà, Marcello. / Analysis of the ATR-Chk1 and ATM-Chk2 pathways in male breast cancer revealed the prognostic significance of ATR expression. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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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.",
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AU - Di Benedetto, Anna

AU - Ercolani, Cristiana

AU - Mottolese, Marcella

AU - Sperati, Francesca

AU - Pizzuti, Laura

AU - Vici, Patrizia

AU - Terrenato, Irene

AU - Shaaban, Abeer M

AU - Humphries, Matthew P

AU - Di Lauro, Luigi

AU - Barba, Maddalena

AU - Vitale, Ilio

AU - Ciliberto, Gennaro

AU - Speirs, Valerie

AU - De Maria, Ruggero

AU - Maugeri-Saccà, Marcello

N1 - 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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N2 - 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.

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