BRCA1 and progesterone receptors in breast cancer

描述(申请人提供)：我们的长期目标是了解BRCA1的组织特异性功能以及它的损伤如何导致乳腺肿瘤的发生。在过去的几十年里，其他人和我们都专注于阐明BRCA1在DNA损伤反应和细胞周期检查点控制中的作用。虽然BRCA1的这种DNA损伤反应功能对肿瘤抑制很重要，但它不能完全解释BRCA1功能异常是如何与遗传性和散发性乳腺癌的加速生长和进展以及乳腺分化障碍相关的。新的证据表明，BRCA1可能是一组不同的基因的转录调节因子，这些基因负责乳腺上皮细胞的增殖和分化。BRCA1与包括雌激素和孕激素受体在内的核激素受体之间的交叉作用为解决组织(乳腺上皮细胞)特有的问题提供了一个潜在的窗口。我们建立了WAP启动子对乳腺上皮细胞BRCA1和P53基因进行特异性消融的小鼠模型。短潜伏期、完全外显性以及与人类乳房病因学的相似性使该小鼠模型非常有价值。有趣的是，伴随着BRCA1的失活，孕激素受体(PR)的表达显著增强。一贯地，用抗孕酮米非司酮(RU486)治疗这些小鼠，可以显著延缓或防止乳腺肿瘤的发生。这一观察结果为通过抗孕酮治疗来预防BRCA1携带者乳腺肿瘤的发生提供了潜在的应用。然而，RU486的复杂性和这种作用的分子机制仍有待解决。目的1.通过确定达到最大疗效所需的最佳剂量和发育窗口，探讨CDB-2914的预防作用机制，并与RU486进行比较，以确定新的抗孕酮CDB-2914预防BRCA1/P53相关乳腺癌发生的有效性。此外，我们计划探索CDB-2914在阻止化疗后肿瘤复发方面的潜力。目的2通过检测PR泛素化是否被GSK-3启动，阐明BRCA1如何调控PR表达的详细机制？研究泛素缺陷型和磷酸化缺陷型PR对细胞增殖的生物学效应以及对BRCA1调控的耐受性。我们期待这项建议取得的成果将为今后乳腺癌的预防和治疗做出重要贡献。公共卫生相关性：我们的长期目标是了解为什么携带BRCA1突变的乳腺上皮细胞对孕酮暴露更敏感，并确定新的抗孕酮是否作为单一药物有效地预防或延缓高危女性乳腺癌的发展。黄体酮受体的活性是如何被调节的将会被研究。这一结果将为乳腺癌的干预提供见解，并将对乳腺癌的预防和治疗具有重要的意义。

DESCRIPTION (provided by applicant): Our long-term goal is to understand the tissue-specific function of BRCA1 and how its impairment leads to breast tumorigenesis. In the past decades, others and we have focused on elucidating roles of BRCA1 in DNA damage response and cell cycle checkpoint control. Although this DNA damage response function of BRCA1 is important for tumor suppression, it fails to fully explain how an aberrant function of BRCA1 is correlated with accelerated growth and progression of hereditary and sporadic breast cancer as well as impairment of mammary gland differentiation. Emerging evidence suggests that BRCA1 may serve as a transcriptional regulator for a diverse group of genes responsible for proliferation and differentiation of mammary epithelial cells. A cross interaction between BRCA1 and nuclear hormone receptors including estrogen and progesterone receptors provides a potential window to address the tissue (mammary epithelial cells)-specific issue. We have established a mouse model in which specific ablation of BRCA1 as well as p53 genes occurred in the mammary epithelial cells by WAP promoter. The short latency, complete penetrance and similarity with human breast etiology make this mouse model very valuable. Interestingly, concomitantly with the inactivation of Brca1, expression of progesterone receptors (PR) was significantly enhanced. Consistently, treatment of these mice with the anti-progesterone, mifepristone (RU486), significantly delays or prevents mammary tumorigenesis. This observation provides a potential application to prevent BRCA1-carrier from breast tumorigenesis by treating with anti-progesterone. However, the complication of RU486 and the molecular mechanism of this effect remain to be addressed. Two specific aims are proposed; Aim 1. To determine the efficacy of the new anti-progesterone, CDB-2914, in preventing Brca1/p53-associated mammary carcinogenesis by determination of the optimal dose and developmental window required for maximal efficacy, investigation of the prevention mechanism of CDB-2914 and comparing with RU486. Furthermore, we plan to explore the potential of CDB-2914 in blocking tumor recurrence after chemotherapeutic treatment. Aim 2 is to elucidate the detailed mechanism of how BRCA1 modulates PR expression by testing whether PR ubiquitination is primed by GSK-3? phosphorylation and investigating the biological effects of ubiquitin-deficient as well as phosphorylation deficient PR on cell proliferation and refractory to BRCA1 regulation. We expect that results obtained from this proposal will make important contributions to the future prevention and treatment of breast cancer. PUBLIC HEALTH RELEVANCE: Our long-term goals are to understand why mammary epithelial cells harboring BRCA1 mutations are more sensitive to progesterone exposure and to determine whether a new anti- progesterone is effective as a single agent for preventing or delaying breast cancer development in high risk women. How the progesterone receptor activity is regulated will be studied. The results will provide insights into breast cancer intervention and will have important implications for in breast cancer prevention and treatment.