El-Tanani Mohamed K, Campbell Frederick Charles, Crowe Paul, Erwin Pauline, Harkin Denis Paul, Pharoah Paul, Ponder Bruce, Rudland Philip S
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Grosvenor Road, Belfast BT12 6BJ, Northern Ireland, United Kingdom.
J Biol Chem. 2006 Sep 8;281(36):26587-601. doi: 10.1074/jbc.M604403200. Epub 2006 Jun 28.
BRCA1 is a well described breast cancer susceptibility gene thought to be involved primarily in DNA repair. However, mutation within the BRCA1 transcriptional domain is also implicated in neoplastic transformation of mammary epithelium, but responsible mechanisms are unclear. Here we show in a rat mammary model system that wild type (WT) BRCA1 specifically represses the expression of osteopontin (OPN), a multifunctional estrogen-responsive gene implicated in oncogenic transformation, particularly that of the breast. WT.BRCA1 selectively binds OPN-activating transcription factors estrogen receptor alpha, AP-1, and PEA3, inhibits OPN promoter transactivation, and suppresses OPN mRNA and protein both from an endogenous gene and a relevant model inducible gene. WT.BRCA1 also inhibits OPN-mediated neoplastic transformation characterized by morphology change, anchorage-independent growth, adhesion to fibronectin, and invasion through Matrigel. A mutant BRCA1 allele (Mut.BRCA1) associated with familial breast cancer lacks OPN suppressor effects, binds to WT.BRCA1, and impedes WT.BRCA1 suppression of OPN. Stable transfection of rat breast tumor cell lines with Mut.BRCA1 dramatically up-regulates OPN protein and induces anchorage independent growth. In human primary breast cancer, BRCA1 mutation is significantly associated with OPN overexpression. Taken together, these data suggest that BRCA1 mutation may confer increased tissue-specific cancer risk, in part by disruption of BRCA1 suppression of OPN gene transcription.
BRCA1是一种已被充分描述的乳腺癌易感基因，主要参与DNA修复。然而，BRCA1转录结构域内的突变也与乳腺上皮的肿瘤转化有关，但其相关机制尚不清楚。在此，我们在大鼠乳腺模型系统中发现，野生型（WT）BRCA1特异性抑制骨桥蛋白（OPN）的表达，OPN是一种多功能雌激素反应基因，与致癌转化有关，尤其是乳腺癌的致癌转化。WT.BRCA1选择性结合激活OPN的转录因子雌激素受体α、AP-1和PEA3，抑制OPN启动子的反式激活，并抑制内源性基因和相关模型诱导基因的OPN mRNA及蛋白表达。WT.BRCA1还抑制以形态改变、不依赖贴壁生长、黏附于纤连蛋白以及穿过基质胶侵袭为特征的OPN介导的肿瘤转化。与家族性乳腺癌相关的突变BRCA1等位基因（Mut.BRCA1）缺乏OPN抑制作用，能与WT.BRCA1结合，并阻碍WT.BRCA1对OPN的抑制。用Mut.BRCA1稳定转染大鼠乳腺肿瘤细胞系可显著上调OPN蛋白表达并诱导不依赖贴壁生长。在人原发性乳腺癌中，BRCA1突变与OPN过表达显著相关。综上所述，这些数据表明，BRCA1突变可能部分通过破坏BRCA1对OPN基因转录的抑制作用而增加组织特异性癌症风险。
