The Mechanism of BRCA1 in Tumor Suppression

描述（由申请人提供）：本提案的长期目标是阐明BRCA1抑制女性乳腺癌和卵巢癌发展的机制。尽管有大量证据表明BRCA1与DNA损伤反应有关，但仍不清楚为什么BRCA1功能的丧失主要增加了雌激素反应组织的癌症风险。最近发表的研究和我们自己的初步数据使我们假设BRCA1可能负性调节芳香酶的组织特异性表达，芳香酶是雌激素生物合成中的限速酶，在乳腺癌的发展中起关键作用。卵巢和乳腺组织脂肪间质细胞BRCA1功能的丧失可能导致循环雌激素和局部雌激素水平升高，从而增加主要雌激素应答组织的癌症风险。这一假说可以解释BRCA1的组织特异性和性别特异性现象。此外，我们的模型预测，卵巢或乳腺组织基质细胞中BRCA1的缺失可能以内分泌或旁分泌的方式促进肿瘤的发展，即使致瘤上皮细胞本身仍然保留BRCA1的功能等位基因。这至少可以部分解释为什么在散发性乳腺癌和卵巢癌中很少发现BRCA1的体细胞突变。为了验证这一假设，我们将通过组织培养细胞中BRCA1的异位表达和siRNA敲低来研究BRCA1对芳香化酶表达的影响。我们还将阐明BRCA1被招募到芳香酶基因的组织特异性启动子的机制。此外，我们将研究BRCA1对芳香化酶启动子转录起始的影响。最后，我们将使用小鼠模型来确定Brcal对体内芳香化酶表达、循环雌激素水平和生殖组织中雌激素依赖性生长的影响。BRCA1和芳香化酶表达之间的潜在联系代表了理解BRCA1肿瘤抑制功能的概念上的进步。鉴于芳香酶抑制剂已成为乳腺癌治疗中最有效的药物之一，本研究有望为诊断和治疗目的提供新的靶点。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to elucidate the mechanism by which BRCA1 suppresses development of breast and ovarian cancers in women. Despite the wealth of evidence that implicates BRCA1 in DNA damage response, it remains unclear as to why loss of BRCA1 function predominantly increases cancer risks in estrogen-responsive tissues. Recent published work and our own preliminary data lead us to the hypothesis that BRCA1 may negatively regulate the tissue-specific expression of aromatase, a rate-limiting enzyme in estrogen biosynthesis and a key player in breast cancer development. Loss of BRCA1 function in ovary and adipose stromal cells in breast tissue may lead to elevated levels of both circulating and local estrogen, thus increasing cancer risks in the major estrogen-responsive tissues. This hypothesis could explain the tissue and gender-specific phenomena of BRCA1. Furthermore, our model predicts that depletion of BRCA1 in ovary or stromal cells in breast tissue may contribute to tumor development in an endocrine or paracrine manner, even when the tumorigenic epithelial cells themselves still retain the functional alleles of BRCA1. This could at least partially explain why somatic mutations of BRCA1 are rarely found in sporadic breast and ovarian cancer. To test this hypothesis, we will study the effect of BRCA1 on aromatase expression by ectopically expression and siRNA knockdown of BRCA1 in tissue culture cells. We will also elucidate the mechanism by which BRCA1 is recruited to the tissue-specific promoter of the aromatase gene. Furthermore, we will investigate the impact of BRCA1 on transcription initiation at the aromatase promoter. Finally we will use mouse models to determine the effect of Brcal on aromatase expression in vivo, circulating estrogen levels, and estrogen-dependent growth in reproductive tissues. The potential link between BRCA1 and aromatase expression represents a conceptual advance in understanding the tumor suppressor function of BRCA1. Given that aromatase inhibitors have become one of the most effective drugs in breast cancer treatment, the proposed work promises to provide novel targets for diagnostic and therapeutic purposes.