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

• 批准号: 10709657
• 负责人: Traci Lyons
• 金额: $ 40.19万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/10709657
• 关键词: Affect; Age; Anoikis; Apoptosis; Autoantigens; Basement membrane; Biological Response Modifiers; Biology; Birth; Breast Cancer Cell; Breast Cancer Patient; 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 Cells; Epithelium; Exhibits; Extracellular Matrix; First Births; Gene Expression Profiling; Gland; Goals; Immune; Immune Tolerance; Immune system; Immunologic Surveillance; Immunosuppression; Integrins; Knockout Mice; Lactation; Length; Lymphatic; Lymphatic Endothelial Cells; Macrophage; Maintenance; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Mediating; Modeling; Modernization; Mus; Natural regeneration; Neuroimmune; Neurons; Phase; Population; Postpartum Period; Postpartum Women; Predisposition; 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; 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

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， 妊娠相关的乳腺变化如何促进乳房发育 癌的虽然众所周知，怀孕对乳腺癌风险有保护作用，但所有女性 每次怀孕后，分娩的女性患乳腺癌的风险会短暂增加。幅度 这种高风险的持续时间在很大程度上取决于妇女第一次生育的年龄， 第一次怀孕时，保护作用可能永远不会发生。产后乳腺癌（PPBC），定义 由于在最近一次分娩后5-10年内诊断出乳腺癌， 转移并导致死亡。这种毁灭性的诊断每年影响约12，000名女性。2006年，为 30多岁生育子女的妇女人数首次超过25岁以下的妇女人数。因此，在本发明中， PPBC案件正在上升。据认为，现代生育做法有助于增加风险， 发展PPBC。我们已经证明，在乳腺癌中，肿瘤细胞和正常相邻的乳腺上皮细胞（MEC） PPBC患者表现出高水平的SEMA 7A表达，并且表达SEMA 7A的肿瘤更多。 转移性的因此，我们认为，了解SEMA 7A信号转导的机制， 乳腺癌将导致新的见解侵略性PPBC。我们最近的初步数据显示 产后退化期间SEMA 7A+活MEC表明SEMA 7A可促进产后退化期间的细胞存活。 产后腺体退化与我们的假设一致，SEMA 7A促进培养的细胞存活。 MEC和我们的初步数据表明，MEC减少，淋巴管内皮细胞（LEC）和 免疫细胞群体的SEMA 7A-/-（KO）小鼠。来自KO小鼠的其他数据显示， 程序性死亡配体-1（PD-L1+），一种我们已经证明对免疫抑制很重要的分子 在退化期间，对乳腺巨噬细胞、LEC和MEC。随着上皮细胞凋亡的发生 在退化过程中，可能导致自身抗原的呈递， 可能是防止自身抗原激活免疫系统所必需的， 乳腺和间质隔室中剩余细胞的存活。我们的首要假设是 SEMA 7A的表达促进了细胞存活，并促进了微环境的短暂耐受。 乳腺;此外，SEMA 7A的异常持续上调可能使女性易于 乳腺恶性肿瘤Aim 1将定义SEMA 7A在乳腺癌期间上皮细胞存活中的作用。 对合Aim 2将破译SEMA 7A介导的乳腺癌免疫耐受机制 产后复旧期间的微环境。相关性：为了确定临床相关性，我们还将 对最近哺乳期妇女的正常乳腺组织进行多色免疫染色。