Hormonal regulation of p53 activity in mammary tissue

乳腺组织中 p53 活性的激素调节

• 批准号: 7365433
• 负责人: D. Joseph Jerry
• 金额: $ 5.44万
• 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/7365433
• 关键词: Breast; Breast Cancer Prevention; Cell Line; Chemopreventive Agent; Complex; DNA Damage; Data; Development; Dissection; Drug usage; Endocrine; Enzymes; Epithelial; Epithelial Cells; Estrogens; Event; Female; Genes; Genetic; Hormonal; Hormones; Inbred BALB C Mice; Incidence; Knockout Mice; Laboratories; Lead; MCF7 cell; Mammary Neoplasms; Mammary gland; Mediating; Metabolism; Modification; Molecular; Molecular Analysis; Molecular Conformation; Mus; Numbers; Organ Culture Techniques; Ovarian; Ovariectomy; Pathway interactions; Pattern; Post-Translational Protein Processing; Predisposition; Progesterone; Prophylactic treatment; Protein Isoforms; Protein p53; Rate; Research Personnel; Resistance; Resolution; Risk; Signal Pathway; Signal Transduction; Small Interfering RNA; Steroid Receptors; Steroids; Stimulus; Stress; TP53 gene; Tissues; Transducers; Transforming Growth Factor beta; Transplantation; Treatment Protocols; Tretinoin; Tumor Suppression; Tumor Suppressor Proteins; Woman; base; carcinogenesis; hormone regulation; in vivo; inhibitor/antagonist; malignant breast neoplasm; mammary epithelium; novel; programs; receptor; research study; response

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.

携带p53通路基因缺陷的女性患乳腺癌的风险极高