BRCA1 and progesterone receptors in breast cancer

描述（由申请人提供）：我们的长期目标是了解BRCA1的组织特异性功能以及其损伤如何导致乳腺肿瘤发生。在过去的几十年里，我们和其他人一直致力于阐明BRCA1在DNA损伤反应和细胞周期检查点控制中的作用。尽管BRCA1的这种DNA损伤反应功能对肿瘤抑制很重要，但它并不能完全解释BRCA1的异常功能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。新出现的证据表明，BRCA1可能是一组负责乳腺上皮细胞增殖和分化的不同基因的转录调节因子。BRCA1与核激素受体（包括雌激素和孕激素受体）之间的交叉相互作用为解决组织（乳腺上皮细胞）特异性问题提供了一个潜在的窗口。我们建立了一个小鼠模型，在该模型中，WAP启动子特异性地消融乳腺上皮细胞中的BRCA1和p53基因。该模型具有潜伏期短、外显率高、与人类乳腺病因学相似等特点。有趣的是，伴随着Brca1的失活，孕激素受体（PR）的表达显著增强。与此一致的是，用抗孕酮米非司酮（RU486）治疗这些小鼠，可显著延缓或防止乳腺肿瘤的发生。这一观察结果为通过抗黄体酮治疗预防brca1携带者的乳腺肿瘤发生提供了潜在的应用。然而，RU486的并发症及其作用的分子机制仍有待研究。提出了两个具体目标；目的1。研究新型抗孕酮CDB-2914对Brca1/p53相关乳腺癌的预防作用，确定其最佳剂量和达到最大疗效所需的发育窗口期，探讨CDB-2914的预防机制，并与RU486进行比较。此外，我们计划探索CDB-2914在阻断化疗后肿瘤复发方面的潜力。目的2是通过检测PR泛素化是否由GSK-3引发，阐明BRCA1如何调节PR表达的详细机制。磷酸化和研究泛素缺乏和磷酸化缺乏的PR对细胞增殖和BRCA1调控难的生物学效应。我们期望从这项建议中获得的结果将对未来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黄体酮暴露更敏感，并确定一种新的抗黄体酮是否能有效地作为单一药物预防或延缓高风险女性乳腺癌的发展。黄体酮受体的活性是如何调控的还有待进一步研究。该结果将为乳腺癌干预提供见解，并对乳腺癌的预防和治疗具有重要意义。

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.