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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

基本信息

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
项目类别：
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

项目摘要

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.

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