Stanley Jennifer, Klepczyk Lisa, Keene Kimberly, Wei Shi, Li Yufeng, Forero Andres, Grizzle William, Wielgos Monica, Brazelton Jason, LoBuglio Albert F, Yang Eddy S
Department of Radiation Oncology, University of Alabama at Birmingham, 1700 6th Avenue South, 176F HSROC Rm 2232 N, Birmingham, AL, USA.
Breast Cancer Res Treat. 2015 Apr;150(3):569-79. doi: 10.1007/s10549-015-3359-6. Epub 2015 Apr 2.
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.
先前的研究表明，基底样乳腺癌可能具有内在的“BRCA样”表型以及对聚（ADP - 核糖）聚合酶（PARP）抑制剂敏感，其PARP1表达水平升高。我们实验室最近报道，HER2阳性乳腺癌通过减弱NF - κB信号通路也对PARP抑制剂（PARPi）敏感。在本研究中，我们评估了PARP1和磷酸化p65（一种活化的NF - κB水平标志物）在人乳腺癌组织中的情况。通过使用cBioPortal查询来自TCGA的PAM - 50定义的乳腺癌患者数据集，评估PARP1和PARP2的拷贝数、mRNA和蛋白表达。使用307例原发性乳腺癌标本（132例基底样、82例管腔型、93例HER2阳性）通过单因素和多因素分析进行PARP1和磷酸化p65免疫组化以及与临床参数的相关性分析。在PAM50乳腺癌数据集中，PARP1和2的表达在24/58（41%）的HER2阳性、32/81（40%）的基底样和75/324（23%）的管腔A/B型乳腺癌患者中发生改变。这与HER2阳性和基底样乳腺癌（分别为p = 0.003，p = 0.027）而非管腔型乳腺癌中PARP1蛋白水平的统计学显著升高相关（p = 0.289）。未观察到PARP2蛋白水平的变化。有趣的是，使用307例患者的乳腺癌标本，HER2阳性与PARP1表达升高相关（p < 0.0001），并且HER2阳性乳腺癌出现高PARP1水平的可能性是HER2阴性乳腺癌的三倍。在PARP1表达的种族、雌激素受体（ER）状态或孕激素受体（PR）状态之间未发现显著差异。此外，我们发现HER2状态与磷酸化p65表达之间存在显著相关性（p < 0.0001）。最后，注意到PARP1与磷酸化p65之间存在直接相关性（p < 0.0001）。这些结果表明HER2、PARP1和磷酸化p65之间存在潜在联系。此外，这些数据表明我们先前在HER2阳性乳腺癌细胞中观察到的PARPi敏感性可能归因于PARP1表达升高。
