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.
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, 1700 6th Avenue South, 176F HSROC Rm 2232 N, Birmingham, AL, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stanley
authors.forename: Lisa
authors.initials: L
authors.lastname: Klepczyk
authors.forename: Kimberly
authors.initials: K
authors.lastname: Keene
authors.forename: Shi
authors.initials: S
authors.lastname: Wei
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.forename: William
authors.initials: W
authors.lastname: Grizzle
authors.forename: Monica
authors.initials: M
authors.lastname: Wielgos
authors.forename: Jason
authors.initials: J
authors.lastname: Brazelton
authors.forename: Albert F
authors.initials: AF
authors.lastname: LoBuglio
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D018719:Erb-b2 Receptor Tyrosine Kinases; D051996:Transcription Factor RelA; C498143:RELA protein, human; C499320:PARP1 protein, human; C508053:ERBB2 protein, human
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