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（由适用提供）：终生孕酮（P4）暴露是导致乳腺癌风险的重要原因，如与终生排卵周期相关的风险所反映的，增加的乳腺上皮增殖涉及黄体期P4峰，以及较高的乳腺癌风险对外生孕激素使用者的风险更高。此外，使用孕激素使用的肿瘤似乎更具侵略性。该临床和流行病学证据表明，孕酮是预防乳腺癌的极好候选策略。现在可以使用新一代的选择性孕酮受体调节剂（SPRMS）。其中一种（替代苯二甲酸酯，TPA）抑制了乳腺癌细胞的P4驱动的增殖，并抑制了致癌物治疗的大鼠中P4驱动的肿瘤生长。我们已经确定了与乳腺癌细胞增殖有关的一组新型基因 TPA有效抑制的孕激素R5020。基于这些数据以及其他发现的结果，我们假设P4促进了支持乳腺癌发展的促增殖和肿瘤允许的表型，SPRMS对乳腺癌的抑制作用将显着降低乳腺癌的风险。潜在的Sprms乳腺癌保护的乳房特异性和机制尚不清楚。我们建议定义Sprms在分子水平上对PR进行拮抗的机制，以及共激活因子和核压剂的作用。此外，将确定SPRMS在对P4的增殖反应拮抗作用中的效率，以指导患者选择SPRM治疗。在AIM 1中，我们将确定SPRMS在乳腺细胞中调节PR活性的机制。 Sprms影响与PR结合的能力将研究；我们将执行CHIP-SEQ，以确定SPRMS如何以全球方式影响PR募集到基因组，并评估核接收器Corepresser，NCOR和SMRT以及其他转录辅助因子的参与。在AIM 2中，我们将确定SPRMS是否抑制P4介导的肿瘤允许表型。我们定义了一个16个基因面板，该基因面板与P4驱动增殖有关。我们将在人类乳腺类器官中在体外测试这一点，以确定SPRMS是否抑制了这些特征基因的表达。我们还将研究SPRMS抑制与P4暴露相关的乳细胞扩张的能力，以及携带BRCA1突变的肿瘤的增殖和生长。在AIM 3中，我们将评估人类临床样品中的表达P4反应基因，a）在高和低环境孕酮环境中，b）用乙酸氨转替酮治疗后。这些实验将1）定义PR信号活性的细胞和组织中SPRM的作用模式，2）将乳腺细胞增殖以及干细胞膨胀的抑制与特定的遗传途径相关联； 3）在人类乳房样品中证明了这些标记的效用。这些结果将大大推动乳腺癌在新方向上的预防领域，从而提供新的，有效的药物，尤其是对于月球前妇女。