Exploring the role of ER Beta in disease penetrance in individuals with Li-Fraumeni syndrome

探索 ER Beta 在 Li-Fraumeni 综合征个体疾病外显率中的作用

• 批准号: 10548896
• 负责人: Christoforos Thomas
• 金额: $ 16.68万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548896
• 关键词: Address; Adolescence; Affect; Aftercare; Age; Agonist; Alleles; Alveolar; Binding; Biological Markers; Biological Process; Brain; Breast; Breast Cancer Prevention; Cells; Chemoprevention; Clinical; Clinical Trials; Collaborations; Complex; DNA Damage; DNA Repair; Development; Differentiation and Growth; Disease; Dominant-Negative Mutation; Embryo; Endocrine; Ensure; Epithelial Cell Proliferation; Epithelial Cells; Equilibrium; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Therapy; Estrogens; Etiology; Evaluation; Family; Female; Fibroblasts; Gene Expression Profiling; Genes; Genome; Genome Stability; Genotoxic Stress; Germ-Line Mutation; Gland; Gonadal Steroid Hormones; Growth; Heterozygote; High-Risk Cancer; Hormones; Human; Impairment; Incidence; Individual; Inherited; Knock-out; Knockout Mice; Lactation; Lead; Li-Fraumeni Syndrome; Ligands; Link; Loss of Heterozygosity; Malignant - descriptor; Malignant Neoplasms; Mammary Duct; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Modeling; Mus; Mutation; Oncogenic; Ovarian hormone; Ovary; Pathway interactions; Penetrance; Phenotype; Predisposition; Pregnancy; Preventive therapy; Proliferating; Puberty; Regimen; Research; Role; Signal Transduction; Specimen; Syndrome; TP53 gene; Testing; Tissues; Tumor Suppressor Proteins; antagonist; breast tumorigenesis; cancer predisposition; cancer risk; cancer type; cell growth; clinical diagnosis; early onset; epidemiology study; gain of function; genome integrity; hormonal signals; improved; in vivo; male; malignant breast neoplasm; mammary; mammary epithelium; metaplastic cell transformation; mortality; mutant; mutation carrier; neoplastic cell; novel; novel chemoprevention; parity; pregnant; prophylactic; receptor; response; tumor; tumorigenesis; tumorigenic

Abstarct Individuals with Li-Fraumeni syndrome (LFS) are predisposed to a wide spectrum of cancer types at a relatively early age. Despite that LFS is linked to germline mutations of p53, these aberrations alone cannot explain the complex phenotype of the syndrome. The observation that female mutation carriers have higher cancer risk than males points to a role of sex steroid signaling in affecting disease penetrance. Further, breast cancer whose etiology relates to aberrant hormonal signaling is the most common malignancy in LFS. However, the effects of irregular hormone signaling on breast tumorigenesis in LFS have not been explored. Estrogen is essential for proper development and function of breast tissue. It regulates proliferation and differentiation of epithelial cells in adolescence and pregnancy. Because cells in development are susceptible to malignant transformation, it is well accepted that the proliferative action of estrogen is coordinated with an increase in genome surveillance. Two receptors (ERα and ERβ) mediate the effects of estrogen in mammary tissue. While ERα is responsible for the proliferative activity of the hormone, ERβ promotes differentiation and regulates DNA damage response which let us to propose that this subtype is employed by estrogen to ensure genome integrity. In support of this role, our findings demonstrate that ERβ enhances the activity of p53 in response to genotoxic stress and loss of synergistic tumor suppressor function as a result of combined inactivation in mammary gland results in early- onset breast tumors in mice. In addition to wild-type form, we have seen that ERβ binds to mutant p53 to inhibit its oncogenic function. Since LFS tissues are often heterozygous for mutant p53, we hypothesize that ERβ coordinates with both alleles of p53 and other pathways to maintain genome stability and, therefore, dysregulation of ERβ signaling in LFS mammary tissue results in malignant transformation and increased incidence of breast cancer. Our proposed research will: 1) investigate whether ERβ affects breast tumorigenesis in LFS, 2) determine effects of ERβ agonists on penetrance in LFS and 3) elucidate the mechanism of ERβ action. To test whether abnormal ERβ signaling affects breast cancer in LFS, we will analyze virgin and pregnant mice with germline point p53 mutations that mimic human LFS phenotypes and ubiquitous and mammary gland- specific inactivation of ERβ. We will also assess ERβ expression in human LFS tissues and identify associations with the age of tumor onset (Aim 1). In addition, we will treat LFS mice with ERβ agonists that are in clinical trials for other diseases expecting these compounds to potentiate its tumor suppressor activity and prevent breast cancer and its associated mortality (Aim 2). Further, we will delineate the mechanisms of ERβ action by analyzing LFS tissues for pathways that are associated with the phenotype of the syndrome (Aim 3). Determining the effects of estrogen signaling on LFS tissues will lead through the development of novel estrogen responsive biomarkers to a better model to predict cancer risk in the syndrome and assist the evaluation of endocrine compounds as a novel chemoprevention regimen to reduce cancer incidence and its associated mortality.

戒酒 Li-Fraumeni综合征（LFS）的个体倾向于相对的广泛癌症类型 年龄。尽管LFS与p53的种系突变有关，但仅这些畸变无法解释 综合征的复杂表型。观察到女性突变携带者的癌症风险高于 男性指出了性类固醇信号在影响疾病外渗中的作用。此外，乳腺癌的乳腺癌 病因涉及异常的骑马信号传导是LFS中最常见的恶性肿瘤。但是， 尚未探索在LFS中乳腺肿瘤发生的不规则骑马信号传导。雌激素对于 乳房组织的正常发育和功能。它调节上皮细胞的增殖和分化 在青少年和怀孕中。因为开发中的细胞容易受到恶性转化的影响，所以 公认的是，雌激素的增殖作用与基因组监测的增加相协调。 两个接收器（ERα和ERβ）介导雌激素在乳腺组织中的影响。而ERα负责 马烯的增殖活性，ERβ促进分化并调节DNA损伤反应 这使我们提出这种亚型是由雌激素用于确保基因组完整性的。支持这个 角色，我们的发现表明，ERβ对遗传毒性应力和丧失的响应增强了p53的活性 由于乳腺中灭活综合失活而导致的协同肿瘤抑制作用导致早期 小鼠的发作乳腺肿瘤。除了野生型形式外，我们还看到ERβ与突变体p53结合以抑制 它的致癌功能。由于LFS组织通常对于突变体P53是杂合的，我们假设ERβ 与p53等位基因和其他途径的坐标，以维持基因组稳定性，因此 LFS乳腺组织中ERβ信号的失调导致恶性转化并增加 乳腺癌的发病率。我们提出的研究将：1）研究ERβ是否影响乳腺肿瘤发生 在LFS中，2）确定ERβ激动剂对LFS渗透的影响，3）阐明ERβ机制 行动。为了测试异常的ERβ信号传导是否影响LFS的乳腺癌，我们将分析处女和怀孕 具有生殖点p53突变的小鼠，它们模仿人LFS表型以及无处不在的乳腺 ERβ的特异性失活。我们还将评估人LFS组织中的ERβ表达并确定关联 随着肿瘤发作的年龄（AIM 1）。此外，我们将使用正在临床试验中的ERβ激动剂治疗LFS小鼠 对于其他期望这些化合物潜在其肿瘤抑制活性并防止乳房的疾病 癌症及其相关的死亡率（AIM 2）。此外，我们将通过分析描述ERβ作用的机制 与综合征表型相关的途径的LFS组织（AIM 3）。确定 雌激素信号对LFS组织的影响将导致新型雌激素反应的发展 生物标志物具有更好的模型，以预测综合征中的癌症风险并帮助评估内分泌 化合物是一种新型化学预防方案，可降低癌症的发生率及其相关的死亡率。