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

Jennifer Stanley; Lisa Klepczyk; Kimberly Keene; Shi Wei; Yufeng Li; Andres Forero; William Grizzle; Monica Wielgos; Jason Brazelton; Albert F. LoBuglio; Eddy S. Yang

doi:10.1007/s10549-015-3359-6

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

Jennifer Stanley
, Lisa Klepczyk
, Kimberly Keene
, Shi Wei
, Yufeng Li
, Andres Forero
, William Grizzle
, Monica Wielgos
, Jason Brazelton
, Albert F. LoBuglio
, Eddy S. Yang

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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.

Original language	English
Pages (from-to)	569-579
Number of pages	11
Journal	Breast Cancer Research and Treatment
Volume	150
Issue number	3
DOIs	https://doi.org/10.1007/s10549-015-3359-6
State	Published - Apr 1 2015

Bibliographical note

Publisher Copyright:
© 2015, Springer Science+Business Media New York.

Funding

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.

Funders	Funder number
AACR-Genentech	12-30-18-YANG
Department of Radiation Oncology	5P50CA 089019, P30CA-13148-41
Minority Biospecimen/Biobanking Geographic Management Program for Region 3	3U54 CA153509-03S1, BMaP-3
NIH/NIGMS	5T32GM008361-21
National Childhood Cancer Registry – National Cancer Institute
National Institute of General Medical Sciences
National Institutes of Health (NIH)
Susan G. Komen Career Catalyst Award	10-16308-03-17-G1, CCR12364491
UAB MSTP
National Institute of General Medical Sciences	T32GM008361
University of Alabama, Birmingham	5T32GM008111-27

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Breast cancer
HER2+
NF-κB
PARP1
p65

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1007/s10549-015-3359-6

Cite this

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title = "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.",

keywords = "Breast cancer, HER2+, NF-κB, PARP1, p65",

author = "Jennifer Stanley and Lisa Klepczyk and Kimberly Keene and Shi Wei and Yufeng Li and Andres Forero and William Grizzle and Monica Wielgos and Jason Brazelton and LoBuglio, \{Albert F.\} and Yang, \{Eddy S.\}",

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language = "English",

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AU - Stanley, Jennifer

AU - Klepczyk, Lisa

AU - Keene, Kimberly

AU - Wei, Shi

AU - Li, Yufeng

AU - Forero, Andres

AU - Grizzle, William

AU - Wielgos, Monica

AU - Brazelton, Jason

AU - LoBuglio, Albert F.

AU - Yang, Eddy S.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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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KW - HER2+

KW - NF-κB

KW - PARP1

KW - p65

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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