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.

Abstarct 患有Li-Fraumeni综合征（LFS）的个体倾向于以相对较低的风险发生广泛的癌症类型。 从小尽管LFS与p53的种系突变有关，但这些畸变本身不能解释LFS的发生。 综合征的复杂表型。女性突变携带者患癌症的风险高于男性， 男性指出性类固醇信号在影响疾病发病率中的作用。此外，乳腺癌， 病因学与异常激素信号传导有关，是LFS中最常见的恶性肿瘤。然而， LFS中乳腺肿瘤发生的不规则激素信号传导尚未研究。雌激素是必不可少的 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 在青春期和怀孕期间。由于发育中的细胞容易发生恶性转化， 雌激素的增殖作用与基因组监视的增加相协调，这一点已被广泛接受。 乳腺组织中有两种受体（ERα和ERβ）介导雌激素的作用。而ERα负责 ER β的增殖活性促进分化并调节DNA损伤反应 这让我们提出，雌激素利用这种亚型来确保基因组的完整性。为支持这一 我们的研究结果表明，ERβ增强了p53的活性，以应对遗传毒性应激和基因缺失。 作为乳腺中联合失活结果的协同肿瘤抑制功能导致早期- 小鼠乳腺肿瘤的发病。除了野生型外，我们还发现ERβ可以与突变型p53结合，抑制 它的致癌功能。由于LFS组织中突变型p53常常是杂合的，我们假设ERβ 与p53和其他途径的等位基因协调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， 乳腺癌的发病率。本研究拟从以下几个方面展开：1）研究ERβ是否影响乳腺肿瘤的发生 在LFS中，2）确定ERβ激动剂对LFS中的抑制率的影响，3）阐明ERβ激动剂对LFS的作用机制。 行动上为了测试异常ERβ信号传导是否影响LFS中的乳腺癌，我们将分析处女和孕妇， 具有生殖系点p53突变的小鼠，其模拟人LFS表型，并且在乳腺和乳腺中普遍存在- ERβ特异性失活。我们还将评估ERβ在人类LFS组织中的表达， 与肿瘤发病年龄相关（目标1）。此外，我们将用临床试验中的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肿瘤抑制活性并预防乳腺癌。 癌症及其相关死亡率（目标2）。进一步，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（目的3）。确定 雌激素信号传导对LFS组织的影响将导致新的雌激素反应性细胞的发展， 生物标志物，以更好的模型来预测癌症风险的综合征，并协助评估内分泌 化合物作为新的化学预防方案来降低癌症发病率及其相关死亡率。