Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells
Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells
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DOI：
10.1038/sj.onc.1205971
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发表时间：
2002-10-31
期刊：
影响因子：
8
通讯作者：
Avraham, HK
中科院分区：
文献类型：
--
作者：
Kawai, H;Li, HC;Avraham, HK
BRCA1突变失活增加乳腺癌风险然而，BRCA1的乳腺组织限制性、肿瘤抑制特性的基础仍然不清楚。在这里，我们表明，BRCA1和雌激素受体α（ER-α）调节血管内皮生长因子（VEGF）基因的转录和乳腺癌细胞的分泌。ER-α在体外和体内与BRCA 1相互作用，这种相互作用由ER-α的AF-2结构域和BRCA 1的两个结构域（氨基酸残基1 - 306和428 - 683）介导。在正常MCF-10A乳腺上皮细胞和乳腺癌细胞（MCF-7和T47D）中观察到ER-α与BRCA 1的内源性相互作用，并且这种相互作用在雌激素存在下显著降低。此外，使用人VEGF启动子-荧光素酶报告基因构建体，ER-α诱导VEGF基因转录的激活。ER-α的AF-2结构域也显示出诱导VEGF基因转录激活，其类似于用全长ER-α获得的。然而，在BRCA1的存在下，VEGF基因的转录激活和VEGF蛋白的分泌以剂量依赖的方式被显著抑制。BRCA1结构域的1 - 683个氨基酸残基是抑制VEGF基因转录激活所必需的。在家族性乳腺癌中发现的BRCA1的三种突变形式（A1708E、M1775R和Y1853X）未能与ER-α相关并抑制VEGF启动子活性和VEGF蛋白分泌。在缺乏内源性功能性BRCA1的HCC-1937乳腺癌细胞中，野生型BRCA1的过表达显著降低了这些细胞中VEGF的分泌。这些结果证明了一种新的致病机制，即BRCA1突变通过与ER-α的相互作用，可以通过乳腺上皮细胞增殖的激素调节和VEGF功能受损促进肿瘤发生，这可能导致癌症生长和血管生成。
Mutational inactivation of BRCA1 confers increased risk for breast cancer. However, the underlying basis for the breast tissue-restricted, tumor-suppressive properties of BRCA1 remains poorly defined. Here, we show that BRCA1 and the estrogen receptor alpha (ER-alpha) modulated vascular endothelial growth factor (VEGF) gene transcription and secretion in breast cancer cells. ER-alpha interacted in vitro and in vivo with BRCA1, and this interaction was mediated by the AF-2 domain of ER-alpha and two domains of BRCA1, the amino-acid residues 1-306 and 428-683. Endogenous interaction of ER-alpha with BRCA1 was observed in normal MCF-10A breast epithelial cells and in breast cancer cells (MCF-7 and T47D), and this interaction was significantly reduced in the presence of estrogen. Furthermore, ER-alpha induced activation of VEGF gene transcription, using human VEGF promoter-luciferase reporter constructs. The AF-2 domain of ER-alpha was also shown to induce VEGF gene transcription activation similar to that obtained with the full-length ER-alpha. However, in the presence of BRCA1, VEGF gene transcription activation and VEGF protein secretion were significantly inhibited in a dose-dependent manner. The BRCA1 domain of 1-683 amino acid residues was required for this inhibition of VEGF gene transcription activation. Three mutated forms of BRCA1 (A1708E, M1775R and Y1853X), that have been identified in familial breast cancers, failed to associate with ER-alpha and to suppress VEGF promoter activity and VEGF protein secretion. Overexpression of wild-type BRCA1 in HCC-1937 breast cancer cells that lack endogenous functional BRCA1 significantly reduced VEGF secretion in these cells. These results demonstrate a novel pathogenic mechanism whereby mutations in BRCA1, via their interaction with ER-alpha, could promote tumorigenesis through the hormonal regulation of mammary epithelial cell proliferation and impaired VEGF function, which may lead to cancer growth and angiogenesis.