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: 10613753
• 负责人: Christoforos Thomas
• 金额: $ 22.33万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10613753
• 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; 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; Genome; Genome Stability; Genotoxic Stress; Germ-Line Mutation; Gland; Gonadal Steroid Hormones; Growth; 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; Pregnancy; Preventive therapy; 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.

抽象 患有 Li-Fraumeni 综合征 (LFS) 的个体相对较容易罹患多种癌症类型。 尽管 LFS 与 p53 种系突变有关，但这些畸变本身并不能解释这一现象。 该综合征的复杂表型观察发现，女性突变携带者的癌症风险高于女性。 男性指出性类固醇信号在影响疾病外显率方面发挥着作用，此外，乳腺癌的发病率也很高。 病因学与激素信号异常有关，是 LFS 中最常见的恶性肿瘤。 雌激素对于 LFS 中乳腺肿瘤发生的作用尚未被探索。 它调节上皮细胞的增殖和分化。 由于发育中的细胞容易发生恶变，因此在青春期和妊娠期。 人们普遍认为，雌激素的增殖作用与基因组监测的增加相协调。 两种受体（ERα 和 ERβ）介导乳腺组织中雌激素的作用。 激素的增殖活性，ERβ促进分化并调节DNA损伤反应 这让我们提出雌激素利用该亚型来确保基因组完整性以支持这一点。 作用，我们的研究结果表明，ERβ 增强了 p53 的活性，以应对基因毒性应激和丧失 由于乳腺联合失活而产生的协同肿瘤抑制功能导致早期 除了野生型形式外，我们还发现 ERβ 与突变型 p53 结合以抑制小鼠发生乳腺肿瘤。 由于 LFS 组织通常是突变 p53 的杂合子，因此我们欺负了 ERβ。 与 p53 等位基因和其他途径协调以维持基因组稳定性，因此， LFS 乳腺组织中 ERβ 信号传导失调会导致恶性转化并增加 我们提出的研究将：1）调查 ERβ 是否影响乳腺肿瘤的发生。 在 LFS 中，2) 确定 ERβ 激动剂对 LFS 外显率的影响，3) 阐明 ERβ 的机制 为了测试 ERβ 信号异常是否会影响 LFS 中的乳腺癌，我们将分析处女和孕妇。 具有模仿人类 LFS 表型和普遍存在的乳腺的种系 p53 突变的小鼠 我们还将评估人类 LFS 组织中 ERβ 的表达并确定关联。 随着肿瘤发病年龄的增加（目标 1），我们将使用处于临床试验阶段的 ERβ 激动剂治疗 LFS 小鼠。 对于其他疾病，期望这些化合物增强其抑制活性并预防乳腺癌 此外，我们将通过分析 ERβ 的作用机制。 LFS 组织中与综合征表型相关的通路（目标 3）。 雌激素信号对 LFS 组织的影响将导致新型雌激素反应性药物的开发 生物标记物可以建立更好的模型来预测该综合征的癌症风险并协助评估内分泌 化合物作为一种新型化学预防方案，可降低癌症发病率及其相关死亡率。