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）：终生黄体酮 (P4) 暴露是乳腺癌风险的一个重要因素，这反映在与终生排卵周期数相关的风险、黄体期 P4 峰值伴随的乳腺上皮增殖增加以及外源性孕激素使用者患乳腺癌的风险更高，此外，使用孕激素时出现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一个很好的选择。新一代选择性黄体酮受体调节剂 (SPRM) 现已上市；其中一种（醋酸特拉司酮，TPA）可抑制 P4 驱动的乳腺癌细胞增殖，并减弱经过致癌剂治疗的 P4 驱动的肿瘤生长。我们已经鉴定出一组与乳腺癌细胞增殖相关的新基因。 TPA 有效抑制孕激素 R5020 基于这些数据以及其他研究结果，我们发现 P4 促进促增殖和肿瘤许可表型，支持乳腺癌的发展，SPRM 抑制该表型将显着减少乳腺癌。 SPRM 的乳腺癌特异性作用和潜在乳腺癌保护机制尚不清楚，我们建议在分子水平上定义 SPRM 拮抗 PR 的机制，以及共激活剂和 PR 的作用。此外，还将确定 SPRM 拮抗 P4 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 调节乳腺细胞中 PR 活性的机制。我们将研究 SPRM 影响 PR 结合的因素；我们将进行 ChIP-Seq 以确定 SPRM 如何以全局方式影响 PR 募集到基因组，以及核受体辅阻遏物、NCOR 和在目标 2 中，我们将评估 SMRT 以及其他转录辅助因子，以确定 SPRM 是否抑制 P4 介导的肿瘤许可表型；我们定义了与 P4 驱动的增殖相关的 16 个基因组。我们还将研究 SPRM 抑制与 P4 暴露相关的乳腺干细胞扩增以及肿瘤增殖和生长的能力。在目标 3 中，我们将评估人类临床样本中 P4 反应基因的表达，a) 在高和低孕酮环境中，b) 在接受醋酸特拉司酮治疗后。 PR 信号传导活跃的细胞和组织中 SPRM 的作用，2) 将乳腺细胞增殖和干细胞扩增的抑制与特定遗传途径联系起来；3) 证明这些标记物在人类中的效用；这些结果将显着推进乳腺癌预防领域的新方向，提供新的、有效的药物，特别是对于绝经前妇女。