Mahmoud Abeer M, Macias Virgilia, Al-Alem Umaima, Deaton Ryan J, Kadjaksy-Balla Andre, Gann Peter H, Rauscher Garth H
College of Applied Health Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
PLoS One. 2017 Sep 1;12(9):e0184385. doi: 10.1371/journal.pone.0184385. eCollection 2017.
Mutations in BRCA1 are associated with familial as well as sporadic aggressive subtypes of breast cancer, but less is known about whether BRCA1 expression or subcellular localization contributes to progression in population-based settings.
We examined BRCA1 expression and subcellular localization in invasive breast cancer tissues from an ethnically diverse sample of 286 patients and 36 normal breast tissue controls. Two different methods were used to label breast cancer tissues for BRCA1: (1) Dual immunofluoresent staining with BRCA1 and cytokeratin 8/18 and (2) immunohistochemical staining using the previously validated MS110 mouse monoclonal antibody. Slides were visualized and quantified using the VECTRA Automated Multispectral Image Analysis System and InForm software.
BRCA1 staining was more intense in normal than in invasive breast tissue for both cytoplasmic (p<0.0001) and nuclear (p<0.01) compartments. BRCA1 nuclear to cytoplasmic ratio was higher in breast cancer cells than in normal mammary epithelial cells. Reduced BRCA1 expression was associated with high tumor grade and negative hormone receptors (estrogen receptor, progesterone receptor and Her2). On the other hand, high BRCA1 expression correlated with basal-like tumors (high CK5/6 and EGFR), and high nuclear androgen receptor staining. Lower nuclear to cytoplasmic ratio of BRCA1 correlated significantly with high Ki67 labeling index (p< 0.05) and family history of breast cancer (p = 0.001).
Findings of this study indicate that alterations in BRCA1 protein expression and subcellular localization in breast cancer correlate with poor prognostic markers and aggressive tumor features. Further large-scale studies are required to assess the potential relevance of BRCA1 protein expression and localization in routine classification of breast cancer.
BRCA1基因突变与家族性及散发性侵袭性乳腺癌亚型相关，但在基于人群的研究中，BRCA1表达或亚细胞定位是否促进疾病进展尚不清楚。
我们检测了286例不同种族患者的浸润性乳腺癌组织及36例正常乳腺组织对照中的BRCA1表达及亚细胞定位。采用两种不同方法标记乳腺癌组织中的BRCA1：（1）BRCA1与细胞角蛋白8/18双重免疫荧光染色；（2）使用先前验证过的MS110小鼠单克隆抗体进行免疫组织化学染色。使用VECTRA自动多光谱图像分析系统和InForm软件对玻片进行观察和定量分析。
在细胞质（p<0.0001）和细胞核（p<0.01）区室中，正常乳腺组织中的BRCA1染色比浸润性乳腺癌组织更强。乳腺癌细胞中BRCA1的核质比高于正常乳腺上皮细胞。BRCA1表达降低与高肿瘤分级及激素受体（雌激素受体、孕激素受体和Her2）阴性相关。另一方面，BRCA1高表达与基底样肿瘤（高CK5/6和EGFR）及高核雄激素受体染色相关。BRCA1较低的核质比与高Ki67标记指数（p<0.05）及乳腺癌家族史（p = 0.001）显著相关。
本研究结果表明，乳腺癌中BRCA1蛋白表达及亚细胞定位的改变与不良预后标志物及侵袭性肿瘤特征相关。需要进一步开展大规模研究，以评估BRCA1蛋白表达及定位在乳腺癌常规分类中的潜在相关性。
