Hormonal regulation of p53 activity in mammary tissue

在携带p53基因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殊重要性。我们的实验室已经证明 乳腺上皮细胞中P53肿瘤抑制蛋白的活性受激素调节。 具体地说，在未分娩的小鼠的乳腺上皮中，P53的活性受到损害，但对 内分泌治疗已被证明使乳腺上皮对癌变具有抵抗力。 初步数据表明，雌激素和孕激素(E-P)都需要治疗！ 乳腺上皮对DNA损伤的P53依赖性反应。我们建议把乳房 在特定的时间段，由于P53活性受损，上皮细胞变得容易癌变 乳腺发育时期，但特定的内分泌刺激用于激活P53 起作用并降低这种风险。本提案中概述的实验将通过以下方式定义路径 E-P对乳腺P53功能有调节作用。目标1：调解的途径 E-P对P53活性的影响将通过确定启动级联反应的受体来检验 (目标1.1)，E-P转导信号的转录靶标(目标1.2)，以及作用于 P53蛋白，使其对DNA损伤诱导的应激信号做出反应(目标1.3)。目的2：荷瘤小鼠 P53状态不同的乳腺上皮移植(BALB/c-Trp53/-vs BALB/c-Trp53-/-)将是 用于确定激素治疗是否通过P53依赖的机制抑制乳腺肿瘤。目标 3：将在整个器官培养中研究依赖E-P激活P53所需的途径 使用药物抑制剂和来自基因敲除小鼠的乳房组织来识别特定的靶点。乳房上皮 细胞系将被用来提供更高分辨率的分子机制分析。基于 初步数据，维甲酸代谢和转化生长因子-β信号的影响将被强调。这个 结果将导致确定调控乳腺中P53功能的细胞机制 上皮组织。这些途径将为乳腺癌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.