Progesterone Signaling and Blockade in Human Breast Tumorigenesis and Prevention

人类乳腺肿瘤发生和预防中的黄体酮信号传导和阻断

• 批准号: 9315776
• 负责人: SEEMA Ahsan KHAN
• 金额: $ 39.62万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-03 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315776
• 关键词: Acetates; Affect; Animals; Attenuated; BRCA1 Mutation; BRCA1 gene; Benign; Binding; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Prevention; Carcinogens; Cell Line; Cell Proliferation; Cells; ChIP-seq; Chromatin; Clinical; Clinical Trials; Collection; Consensus Sequence; Contraceptive methods; Data; Development; Early treatment; Environment; Epidemiology; Epithelial; Exposure to; FVB Mouse; Funding; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Genome; Genomics; Gynecology; Hormones; Human; Knockout Mice; Laboratory Finding; Luteal Phase; Mammaplasty; Mammary Gland Parenchyma; Mammary gland; Measures; Mediating; Medroxyprogesterone 17-Acetate; Menopausal Symptom; Molecular; Molecular Mechanisms of Action; Nuclear Receptors; Operative Surgical Procedures; Organoids; Pathway interactions; Patient Selection; Phenotype; Physiological; Premenopause; Prevention; Prevention strategy; Progesterone; Progesterone Receptors; Progestins; RU-5020; Rattus; Receptor Signaling; Recruitment Activity; Risk; Role; Safety; Sampling; Series; Signal Transduction; Specimen; Stem cells; TNFSF11 gene; Tamoxifen; Testing; Tissue Banks; Tissues; Woman; base; breast tumorigenesis; cancer risk; candidate marker; cofactor; efficacy testing; experience; experimental study; gene panel; genetic signature; high risk; hormone therapy; in vitro testing; laboratory experiment; malignant breast neoplasm; mouse model; novel; permissiveness; pre-clinical; prevent; public health relevance; receptor; response; stem cell division; tumor; tumor growth

 DESCRIPTION (provided by applicant): Lifetime progesterone (P4) exposure is an important contributor to breast cancer risk, as reflected in the risk associated with the lifetime number of ovulatory cycles, increased breast epithelial proliferation accompanying the P4 peak in the luteal phase, and the higher breast cancer risk of exogenous progestin users. Moreover, the tumors seen with progestin use appear to be more aggressive. This clinical and epidemiological evidence points to progesterone blockade as an excellent candidate strategy for breast cancer prevention. A new generation of selective progesterone receptor modulators (SPRMs) is now available; one of these (telapristone acetate, TPA) inhibits P4-driven proliferation of breast cancer cells, and attenuates P4-driven tumor growth in carcinogen treated rats. We have identified a novel set of genes associated with proliferation of breast cancer cells in response to the progestin, R5020 that are effectively suppressed by TPA. Based on these data as well as findings from others, we hypothesize that P4 promotes a pro-proliferative and tumor permissive phenotype which supports breast cancer development, suppression of which by SPRMs will significantly decrease breast cancer risk. The breast-specific effects and mechanisms for potential breast cancer protection of SPRMs are unknown. We propose to define the mechanisms by which SPRMs antagonize PR at the molecular level, and the role of coactivators and corepressors. In addition, the efficacy of SPRMs in antagonizing the proliferative response to P4 will be determined, to guide selection of patients for SPRM therapy. In Aim 1, we will determine the mechanisms by which SPRMs regulate PR activity in breast cells. The ability of SPRMs to affect binding to the PR will be studied; we will perform ChIP-Seq to determine how SPRMs affect PR recruitment to the genome in a global manner, and the involvement of the nuclear receptor corepressors, NCOR and SMRT as well as other transcription cofactors will be assessed. In Aim 2, we will determine if SPRMs inhibit the P4-mediated tumor permissive phenotype; we have defined a 16 gene panel, which is associated with P4 driven proliferation. We will test this in vitro, in human mammary organoids, to determine whether SPRMs inhibit expression of these signature genes. We will also study the ability of SPRMs to inhibit mammary stem cell expansion associated with P4 exposure, and the proliferation and growth of tumors that carry BRCA1 mutations. In Aim 3, we will evaluate the expression P4-response genes in human clinical samples, a) in high and low ambient progesterone environments and b) following treatment with telapristone acetate. These experiments will 1) define modes of actions of SPRMs in cells and tissues where PR signaling is active, 2) relate inhibition of proliferation of breast cells, and of stem cell expansion, to speciic genetic pathways; and 3) demonstrate utility of these markers in human breast samples. These results will significantly advance the field of breast cancer prevention in novel directions, providing both new, effective agents, particularly for premenopausal women.

 描述（由申请人提供）：终身孕酮（P4）暴露是乳腺癌风险的重要因素，反映在与排卵周期的终身数量相关的风险、黄体期P4峰值伴随的乳腺上皮增殖增加以及外源性孕酮使用者的较高乳腺癌风险中。此外，使用白蛋白所观察到的肿瘤似乎更具侵袭性。这一临床和流行病学证据表明，孕激素阻断是预防乳腺癌的一个很好的候选策略。新一代的选择性孕酮受体调节剂（SPRM）现在是可用的，其中之一（醋酸特拉司酮，TPA）抑制P4驱动的乳腺癌细胞的增殖，并减弱P4驱动的肿瘤生长在致癌物治疗的大鼠。我们已经确定了一组与乳腺癌细胞增殖相关的新基因， TPA能有效抑制R5020的表达。基于这些数据以及其他人的发现，我们假设P4促进了支持乳腺癌发展的促增殖和肿瘤容许表型，SPRM对其的抑制将显著降低乳腺癌风险。SPRM的乳腺特异性作用和潜在乳腺癌保护机制尚不清楚。我们建议定义SPRM在分子水平上拮抗PR的机制，以及辅激活子和辅抑制子的作用。此外，将确定SPRM拮抗对P4的增殖反应的功效，以指导选择SPRM治疗的患者。在目标1中，我们将确定SPRM调节乳腺细胞PR活性的机制。将研究SPRM影响与PR结合的能力;我们将进行ChIP-Seq以确定SPRM如何以全局方式影响PR向基因组的募集，并将评估核受体辅阻遏物、NCOR和SMRT以及其他转录辅因子的参与。在目标2中，我们将确定SPRM是否抑制P4介导的肿瘤容许表型;我们已经定义了一组16个基因，其与P4驱动的增殖相关。我们将在人类乳腺类器官中进行体外测试，以确定SPRM是否抑制这些特征基因的表达。我们还将研究SPRM抑制与P4暴露相关的乳腺干细胞扩增的能力，以及携带BRCA 1突变的肿瘤的增殖和生长。在目的3中，我们将评估人临床样品中P4应答基因的表达，a）在高和低周围孕酮环境中和B）在用醋酸特拉司酮处理后。这些实验将1）定义SPRM在PR信号传导活跃的细胞和组织中的作用模式，2）将乳腺细胞增殖和干细胞扩增的抑制与特异性遗传途径相关联;和3）证明这些标记物在人类乳腺样品中的效用。这些结果将大大推进乳腺癌预防领域的新方向，提供新的，有效的药物，特别是对绝经前妇女。