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SEMA7A in postpartum mammary gland development and cellular transformation

SEMA7A 在产后乳腺发育和细胞转化中的作用

基本信息

批准号：
10594359
负责人：
Traci Lyons
金额：
$ 40.62万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2022-09-22 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594359
关键词：
Affect Age Anoikis Apoptosis Autoantigens Basement membrane Biological Response Modifiers Biology Birth Breast Cancer Risk Factor Breast Epithelial Cells Cell Compartmentation Cell Death Cell Survival Cells Cessation of life Chemotaxis Child Childbirth Chronic Color Data Development Diagnosis Elderly Endothelial Cells Epithelial Epithelial Cells Exhibits Extracellular Matrix First Births Gene Expression Profiling Gland Goals Immune Immune Tolerance Immune system Immunologic Surveillance Immunosuppression Integrins Knockout Mice Lactation Lead Length Lymphatic Lymphatic Endothelial Cells Maintenance Malignant Neoplasms Mammary Gland Parenchyma Mammary gland Mediating Modeling Modernization Mus Natural regeneration Neuroimmune Neurons Patients Phase Population Postpartum Period Postpartum Women Pregnancy Resistance Risk Role Semaphorins Signal Transduction T-Lymphocyte Testing Time Tissues Up-Regulation Woman breast cancer diagnosis breast malignancies child bearing clinically relevant defined contribution experience functional plasticity immune activation immune clearance immunoregulation in vivo insight macrophage malignant breast neoplasm mammary mammary epithelium mammary gland development metaplastic cell transformation monocyte neoplastic cell novel postnatal development postpartum breast cancer prevent programmed cell death ligand 1 programmed cell death protein 1 protective effect receptor recruit stem cell population stem cells suckling trafficking tumor tumorigenic young woman

项目摘要

Background: We seek to further our understanding of normal mammary gland biology and determine how pregnancy associated changes in the mammary gland may contribute to development of breast cancers. Though pregnancy is well-known to provide a protective effect against breast cancer risk, all women who give birth experience a transient increase in breast cancer risk following each pregnancy. The magnitude and length of this elevated risk is largely determined by the woman's age at first birth and for women over 30 at the time of first pregnancy the protective effect likely never occurs. Postpartum breast cancers (PPBC), defined as breast cancers diagnosed within 5-10 years of last childbirth, are more than twice as likely to become metastatic and result in death. This devastating diagnosis affects ~12,000 women annually. In 2006, for the first time, the number of women having children in their 30s was greater than the number under 25. Thus, PPBC cases are rising. It is thought that modern childbearing practices contribute to the increased risk for developing PPBC. We have shown that tumor cells and normal adjacent mammary epithelial cells (MECs) in PPBC patients exhibit high levels of SEMA7A expression, and SEMA7A expressing tumors are more metastatic. Thus, we believe that understanding the mechanisms underlying SEMA7A signaling in the mammary gland will lead to novel insights into aggressive PPBC. Our recent preliminary data reveal SEMA7A+ live MECs during postpartum involution suggesting that SEMA7A may promotes cell survival during postpartum glandular regression. Consistent with our hypothesis, SEMA7A promotes cell survival in cultured MECs and our preliminary data suggest a reduction in MECs, as well as lymphatic endothelial cells (LECs) and immune cell populations, in SEMA7A-/- (KO) mice. Additional data from KO mice reveal a decrease in programmed death ligand-1 (PD-L1+), a molecule that we have shown to be important for immunosuppression during involution, on mammary macrophages, LECs and MECs. As the epithelial cell apoptosis that occurs during involution likely results in presentation of self-antigens, an immune-tolerant tissue microenvironment may be necessary to prevent activation of the immune system by self-antigens and to simultaneously support survival of remaining cells in the mammary and stromal compartments. Our overarching hypothesis is that SEMA7A expression promotes cell survival and a transiently tolerant microenvironment in the mammary gland; furthermore, aberrant sustained upregulation of SEMA7A may pre-dispose women to breast malignancy. Aim1 will define the role of SEMA7A in epithelial cell survival during mammary gland involution. Aim2 will decipher SEMA7A mediated mechanisms of immune tolerance in the mammary microenvironment during postpartum involution. Relevance: To establish clinical relevance, we will also perform multi-color immunostaining on normal mammary tissues from recently lactating women.

背景：我们寻求进一步了解正常乳腺生物学和确定