PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers

Abstract

Previous studies have shown that basal breast cancers, which may have an inherent “BRCAness” phenotype and sensitivity to inhibitors of poly (ADP-Ribose) polymerase (PARP), express elevated levels of PARP1. Our lab recently reported that HER2+ breast cancers also exhibit sensitivity to PARP inhibitors (PARPi) by attenuating the NF-κB pathway. In this study, we assessed PARP1 and phospho-p65, a marker of activated NF-κB levels in human breast cancer tissues. PARP1 and PARP2 copy number, mRNA, and protein expression was assessed by interrogating the PAM-50 defined breast cancer patient set from the TCGA using cBioPortal. PARP1 and phospho-p65 immunohistochemistry and correlation to clinical parameters was conducted using 307 primary breast cancer specimens (132 basal, 82 luminal, 93 HER2+) through univariate and multivariate analyses. In the PAM50 breast cancer data set, PARP1 and 2 expression was altered in 24/58 (41 %) HER2+, 32/81 (40 %) basal, and 75/324 (23 %) luminal A/B breast cancer patients. This correlated with a statistically significant increase in PARP1 protein levels in HER2+ and basal but not luminal breast cancers (p = 0.003, p = 0.027, p = 0.289, respectively). No change in PARP2 protein level was observed. Interestingly, using breast cancer specimens from 307 patients, HER2 positivity correlated with elevated PARP1 expression (p < 0.0001) and was three times more likely than HER2 negative breast cancers to exhibit high PARP1 levels. No significant differences were noted between race, ER status, or PR status for PARP1 expression. Additionally, we found a significant correlation between HER2 status and phospho-p65 expression (p < 0.0001). Lastly, a direct correlation between PARP1 and phospho-p65 (p < 0.0001) was noted. These results indicate a potential connection between HER2, PARP1, and phospho-p65. Furthermore, these data suggest that the PARPi sensitivity we previously observed in HER2+ breast cancer cells may be due to elevated PARP1 expression.

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Acknowledgments

This work is supported in part by the Minority Biospecimen/Biobanking Geographic Management Program for Region 3 (BMaP-3) (3U54 CA153509-03S1) (ESY), AACR-Genentech BioOncology Career Development Award for Cancer Research on the HER Family Pathway (12-30-18-YANG, to ESY), Susan G. Komen Career Catalyst Award (CCR12364491, to ESY), NCI/H. Lee Moffitt Cancer Center BMaP Pilot Grant (10-16308-03-17-G1, to ESY), the UAB MSTP (NIH-NIGMS 5T32GM008361-21) (JAS), the UAB Cell and Molecular Biology Training grant (5T32GM008111-27) (JAS), and an intramural pilot grant from the Department of Radiation Oncology (to LK). This work was also supported by the Breast SPORE (5P50CA 089019) and Tissue Procurement Shared Facility (P30CA-13148-41) of the Comprehensive Cancer Center at UAB.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The experiments in this manuscript comply with the current laws of the country in which they were performed.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Correspondence to Eddy S. Yang.

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Jennifer Stanley and Lisa Klepczyk have contributed equally to this work.

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Stanley, J., Klepczyk, L., Keene, K. et al. PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers. Breast Cancer Res Treat 150, 569–579 (2015). https://doi.org/10.1007/s10549-015-3359-6

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Keywords

  • PARP1
  • p65
  • HER2+
  • NF-κB
  • Breast cancer