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BRCA 1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，其他人和我们一直致力于阐明BRCA 1在DNA损伤反应和细胞周期检查点控制中的作用。尽管BRCA 1的这种DNA损伤反应功能对于肿瘤抑制很重要，但它未能完全解释BRCA 1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受损相关。新出现的证据表明，BRCA 1可能作为一个转录调节器的一组不同的基因负责乳腺上皮细胞的增殖和分化。BRCA 1和核激素受体（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，乳腺上皮细胞中的BRCA 1和p53基因发生特异性消融WAP启动子。该模型潜伏期短、潜伏期完全、与人乳腺癌病因相似，具有很高的临床应用价值。有趣的是，伴随着Brca 1的失活，孕酮受体（PR）的表达显着增强。因此，用抗孕酮米非司酮（RU 486）治疗这些小鼠，显著延迟或预防乳腺肿瘤发生。这一观察结果提供了一个潜在的应用，以防止BRCA 1载体从乳腺肿瘤的治疗与抗孕激素。然而，RU 486的并发症和这种作用的分子机制仍有待解决。提出了两个具体目标：目标1。通过确定最大功效所需的最佳剂量和发育窗口，研究新型抗孕酮药物CDB-2914预防Brca 1/p53相关乳腺癌发生的功效，并与RU 486进行比较。此外，我们计划探索CDB-2914在化疗后阻断肿瘤复发的潜力。目的二是通过检测PR泛素化是否由GSK-3启动，阐明BRCA 1调控PR表达的详细机制。磷酸化和研究泛素缺陷以及磷酸化缺陷的PR对细胞增殖和对BRCA 1调节难治的生物学作用。我们期望从这一建议中获得的结果将为未来乳腺癌的预防和治疗做出重要贡献。

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.