Hormonal regulation of p53 activity in mammary tissue

乳腺组织中 p53 活性的激素调节

• 批准号: 7050156
• 负责人: D. Joseph Jerry
• 金额: $ 27.93万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050156
• 关键词: DNA damage; RNA interference; biological signal transduction; breast neoplasms; cancer prevention; chemoprevention; conformation; enzyme activity; estrogens; female; genetic transcription; genetically modified animals; hormone regulation /control mechanism; hormone related neoplasm /cancer; laboratory mouse; mammary epithelium; microarray technology; neoplasm /cancer genetics; neoplasm /cancer pharmacology; ovariectomy; p53 gene /protein; posttranslational modifications; progesterone; protein structure function; retinoate; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): The extreme risk of breast cancer among women bearing genetic deficiencies in the p53 pathway reveals the particular importance of p53 in breast cancer susceptibility. Our laboratory has demonstrated that the activity of the p53 tumor suppressor protein in the mammary epithelium is subject to hormonal regulation. Specifically, p53 activity is compromised in mammary epithelium of nulliparous mice, but is responsive to endocrine treatments that have been shown to render the mammary epithelium resistant to carcinogenesis. Preliminary data demonstrate that treatment with both estrogen and progesterone (E+P) are required for p53-dependent responses to DNA damage in the mammary epithelium. We propose that the mammary epithelium is rendered susceptible to carcinogenesis due to impaired p53 activity during specific periods of mammary gland development, but that specific endocrine stimuli serve to activate p53 function and mitigate this risk. The experiments outlined in this proposal will define the pathways by which treatment with E+P regulate p53 function in the mammary gland. Aim 1: The pathways that mediate the effects of E+P on p53 activity will be examined by determining the receptors that initiate the cascade (Aim 1.1), the transcriptional targets of E+P that transduce the signal (Aim 1.2), and the enzymes that act on p53 protein to render it responsive to DNA damage-induced stress signals (Aim 1.3). Aim 2: Mice bearing transplants of mammary epithelium that vary in p53 status (BALB/c-Trp53+/- vs BALB/c-Trp53-/-) will be used to determine whether hormonal treatments inhibit mammary tumors by p53-dependent mechanisms. Aim 3: The pathways necessary for E+P-dependent activation of p53 will be examined in whole organ cultures using drug inhibitors and mammary tissue from knockout mice to identify specific targets. Breast epithelial cell lines will be used to provide higher resolution analysis of the molecular mechanisms. Based on preliminary data, the effects of retinoic acid metabolism and TGF-beta signaling will be emphasized. The results will lead to identification of cellular mechanisms that regulate p53 function in the mammary epithelium. These pathways will provide novel targets for both treatment and prevention of breast cancer.

描述（由申请人提供）：在p53通路中携带遗传缺陷的女性中患乳腺癌的极端风险揭示了p53在乳腺癌易感性中的特别重要性。我们的实验室已经证明，乳腺上皮中的p53肿瘤抑制蛋白的活性受激素调节。具体而言，p53活性在未经产小鼠的乳腺上皮中受损，但对已显示使乳腺上皮对致癌作用具有抗性的内分泌治疗有反应。初步数据表明，治疗与雌激素和孕激素（E+P）的p53依赖性反应，在乳腺上皮细胞的DNA损伤是必需的。我们建议，乳腺上皮细胞是由于受损的p53活性在特定时期的乳腺发育致癌，但特定的内分泌刺激激活p53功能，减轻这种风险。本提案中概述的实验将确定E+P治疗调节乳腺中p53功能的途径。目标1：通过确定启动级联反应的受体（目的1.1）、抑制信号的E+P转录靶点（目的1.2）和作用于p53蛋白使其响应DNA损伤诱导的应激信号的酶（目的1.3），将检查介导E+P对p53活性的影响的途径。目标二：携带p53状态不同的乳腺上皮移植物（BALB/c-Trp 53 +/- vs BALB/c-Trp 53-/-）的小鼠将用于确定激素治疗是否通过p53依赖性机制抑制乳腺肿瘤。目标3：将使用药物抑制剂和来自敲除小鼠的乳腺组织在整个器官培养物中检查p53的E+ P依赖性激活所必需的途径，以鉴定特定靶点。乳腺上皮细胞系将用于提供更高分辨率的分子机制分析。基于初步数据，将强调视黄酸代谢和TGF-β信号传导的影响。结果将导致识别的细胞机制，调节p53在乳腺上皮细胞的功能。这些途径将为乳腺癌的治疗和预防提供新的靶点。