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：我们试图加深对正常乳腺生物学的理解，并确定 与怀孕相关的乳腺变化如何有助于乳房的发育 癌症。尽管众所周知，怀孕可以预防乳腺癌风险，但所有女性 每次怀孕后，生孩子的人患乳腺癌的风险都会有短暂的增加。震级 这种风险升高的持续时间在很大程度上取决于女性第一次生育的年龄，对于30岁以上的女性来说 第一次怀孕的时候，这种保护作用可能永远不会发生。产后乳腺癌(PPBC)，定义 因为在最后一次生育后5-10年内被诊断为乳腺癌，患乳腺癌的可能性是女性的两倍以上 转移并导致死亡。这一毁灭性的诊断每年影响约12,000名女性。在2006年，对于 第一次，30多岁生孩子的女性人数超过了25岁以下的人数。因此， PPBC案件正在上升。据认为，现代生育习惯增加了患糖尿病的风险。 发展PPBC。我们已经证明，肿瘤细胞和正常的邻近乳腺上皮细胞(MECs)在 PPBC患者的SEMA7A表达水平较高，且表达SEMA7A的肿瘤 转移性的。因此，我们认为理解SEMA7A信号转导的机制 乳腺将导致对侵袭性PPBC的新见解。我们最近的初步数据显示 SEMA7A+活的MECs在产后退化期提示SEMA7A可能促进细胞在 产后腺退行性变。与我们的假设一致，SEMA7A促进培养的细胞存活 MECs和我们的初步数据表明，MECs以及淋巴管内皮细胞(LECs)和 SEMA7A-/-(KO)小鼠的免疫细胞群。来自KO小鼠的其他数据显示， 程序性死亡配体-1(PD-L1+)，一个我们已经证明在免疫抑制中起重要作用的分子 退化过程中，乳腺巨噬细胞、LECs和MECs。作为发生的上皮细胞的凋亡 在退化过程中，可能会导致自身抗原的出现，这是一个免疫耐受的组织微环境 可能是防止自身抗原激活免疫系统和同时支持 乳腺和间质间隔中剩余细胞的存活。我们最重要的假设是 SEMA7A表达促进细胞存活和瞬时耐受微环境 此外，SEMA7A的异常持续上调可能会使女性预先患上 乳房恶性肿瘤。AIM1将确定SEMA7A在乳腺上皮细胞存活中的作用 内卷曲。AIM2将破译SEMA7A介导的乳腺免疫耐受机制 产后复旧的微环境。相关性：为了建立临床相关性，我们还将 对最近哺乳妇女的正常乳腺组织进行多色免疫染色。