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.

放弃 Li-Fraumeni综合征(LFS)患者在相对较短的时间内易患多种癌症类型 很小的时候。尽管LFS与P53的胚系突变有关，但这些异常本身并不能解释 该综合征的复杂表型。观察到女性突变携带者患癌症的风险高于 男性指出，性类固醇信号在影响疾病外显性方面发挥了作用。此外，乳腺癌的 病因学与激素信号异常是LFS最常见的恶性肿瘤有关。然而，它的影响 不规则激素信号在LFS乳腺肿瘤发生中的作用尚不清楚。雌激素对人体健康至关重要 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 在青春期和妊娠期。因为发育中的细胞容易发生恶性转化，所以 众所周知，雌激素的增殖作用与基因组监测的增加是相协调的。 ER-α和ER-β两种受体介导雌激素在乳腺组织中的作用。而ERα负责 雌激素受体β的增殖活性促进分化并调节dna损伤反应。 这让我们可以提出，雌激素利用这个亚型来确保基因组的完整性。为了支持这一点 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 乳腺联合失活所致的协同抑癌功能导致早期- 小鼠乳腺肿瘤的发病情况。除了野生型外，我们已经看到ERβ与突变型P53结合来抑制 它的致癌作用。由于LFS组织经常是突变型P53的杂合子，我们假设ERβ 与P53的等位基因和其他途径协调以维持基因组的稳定，因此， 乳腺组织中ERβ信号的失调导致恶变和增加 乳腺癌的发病率。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)测定ERβ激动剂对LFS外显率的影响；3)阐明ERβ的作用机制 行动。为了测试ERβ信号异常是否影响LFS中的乳腺癌，我们将分析处女和怀孕 具有模拟人类LFS表型和无处不在的乳腺的胚系点p53突变的小鼠- ERβ的特异性失活。我们还将评估ERβ在人类脂肪组织中的表达，并确定两者之间的关联 随着肿瘤发病年龄的增加(目标1)。此外，我们将用处于临床试验中的ERβ激动剂来治疗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，防止乳房 癌症及其相关死亡率(目标2)。此外，我们将通过分析ERβ的作用机制来描述它的作用机制 LFS组织，用于与该综合征表型相关的通路(目标3)。确定 雌激素信号在LFS组织中的作用将导致新的雌激素反应的发展 生物标志物更好地预测综合征的癌症风险并辅助内分泌评估 化合物作为一种新的化学预防方案，可降低癌症发病率及其相关死亡率。