Hormonal regulation of p53 activity in mammary tissue

p53 通路遗传缺陷的女性患乳腺癌的风险极高 p53 在乳腺癌易感性中特别重要。我们的实验室已经证明 乳腺上皮中 p53 肿瘤抑制蛋白的活性受到激素调节。 具体来说，p53 活性在未产小鼠的乳腺上皮中受到损害，但对 内分泌治疗已被证明可以使乳腺上皮细胞抵抗癌变。 初步数据表明，需要同时使用雌激素和黄体酮 (E P) 进行治疗！ p53 依赖性对乳腺上皮 DNA 损伤的反应。我们建议乳腺 由于 p53 活性受损，上皮细胞在特定的过程中变得容易致癌。 乳腺发育的时期，但特定的内分泌刺激可以激活 p53 发挥作用并减轻这种风险。本提案中概述的实验将通过以下方式定义途径 E P 治疗可调节乳腺中的 p53 功能。目标 1：调解途径 E P 对 p53 活性的影响将通过确定启动级联的受体来检查 （目标 1.1）、转导信号的 E P 转录靶标（目标 1.2）以及作用于 p53 蛋白使其对 DNA 损伤引起的应激信号做出反应（目标 1.3）。目标 2：小鼠轴承 p53 状态不同的乳腺上皮移植（BALB/c-Trp53 /- vs BALB/c-Trp53-/-）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 图 3：将在整个器官培养物中检查 E P 依赖性 p53 激活所需的途径 使用药物抑制剂和基因敲除小鼠的乳腺组织来识别特定目标。乳腺上皮细胞 细胞系将用于提供更高分辨率的分子机制分析。基于 根据初步数据，将强调视黄酸代谢和 TGF-β 信号传导的影响。的 结果将有助于确定调节乳腺中 p53 功能的细胞机制 上皮。这些途径将为乳腺疾病的治疗和预防提供新的靶点。 癌症。

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 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.