Progesterone promotes mammary gland tumorigenesis through immunosuppressive effects on dendritic cells

黄体酮通过对树突状细胞的免疫抑制作用促进乳腺肿瘤发生

基本信息

批准号：
10626769
负责人：
Lauryn Rose Werner
金额：
$ 3.55万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
2022-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626769
关键词：
Affect Animal Model Anti-Progestin Biological Assay Breast Cancer Cell Breast Epithelial Cells Cancer Etiology Cell Separation Cell physiology Cells Cessation of life Clinical Trials Cross-Priming Cytokine Signaling Data Dendritic Cells Dendritic cell activation Detection Development Diphtheria Toxin Environment Enzyme-Linked Immunosorbent Assay Epithelial Cells Exhibits Female Flow Cytometry Growth Growth and Development function Hormones Human Immune Immune Tolerance Immune signaling Immune system Immunosuppression In Vitro Individual Infiltration Interferon Type I Invaded Lead Link Literature Malignant Neoplasms Mammary gland Measures Mediating Modeling Mus Placebos Play Progesterone Progesterone Receptors Progestins Public Health Publications Publishing RNA analysis Receptor Signaling Reporting Repression Research Risk Role Sampling Signal Pathway T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Transgenic Mice Tumor Antigens Tumor Promotion Western Blotting Work anti-tumor immune response candidate identification chemokine comparison control cytokine genetic signature immune clearance immunoregulation in vivo insight malignant breast neoplasm mammary gland development mouse model neoplastic cell novel overexpression receptor expression recruit single-cell RNA sequencing tool tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

ABSTRACT Breast cancer is the second most common cause of cancer-related death and most common cancer occurring in females in the U.S. Numerous large-scale clinical trials have demonstrated that use of exogenous progestins (synthetic progesterone [P4]) increases the risk of invasive breast cancer in females. Although it has been clearly established in the literature that P4 plays a role in the development of human breast cancer, the mechanism by which P4 promotes breast cancer tumorigenesis remains unknown. Recently, we reported a link between progesterone receptor (PR) and immune signaling pathways. Our recent publications have demonstrated that P4/PR can repress type I interferon signaling pathways in human breast cancer cells. Given these findings, we sought to investigate whether P4/PR drive immunomodulation in the mammary gland to promote formation of mammary gland tumors. Therefore, the central hypothesis of this proposal is that P4 and PR decrease recruitment and function of DCs in the mammary gland, which promotes immunosuppression and subsequent development and growth of mammary gland tumors. We will address this hypothesis through the following specific aims: 1) Define the mechanism by which P4 treatment and PR expression affect DC recruitment to the murine mammary gland and PR+ mammary gland tumors; 2) Characterize the maturation and activity state of DCs isolated from P4-treated PR+ mammary gland tumors; and 3) Determine the contribution of P4-mediated DC suppression to mammary gland tumor growth. For aim 1, we will utilize single cell RNA sequencing (scRNA-seq) to determine if P4 affects the release of cytokines involved in DC recruitment to mammary gland tumor cells. In aim 2, we will determine how P4 treatment affects the activity and function of tumor-infiltrating DCs using syngeneic tumor models, in which markers will be measured via scRNA-seq, flow cytometry, and T cell proliferation assays. Aim 3 will utilize transgenic mouse models to determine whether depletion of DCs impacts P4’s growth-promoting effects on mammary gland tumors. Successful completion of the proposed work will provide novel insight into immune tolerance mechanisms promoting the development and growth of breast cancers. Additionally, it will provide a rationale to target P4/PR signaling with anti-progestins to promote DC function and enhance immune-mediated elimination of tumor cells.

抽象的乳腺癌是癌症相关死亡的第二大最常见原因，最常见的癌症发生在美国的女性中，许多大规模临床表明使用外源孕激素（合成孕酮[P4]）增加了女性侵入性乳腺癌的风险。在文献中清楚地确定了P4在人类乳腺癌的发展中起作用 P4促进乳腺癌肿瘤发生的机制最近未知。孕酮受体（PR）和免疫信号通路之间证明P4/PR可以在人类乳腺癌细胞中抑制I型干扰素信号通路这些发现，我们试图研究乳腺中的P4/PR驱动免疫调节促进乳腺肿瘤的形成。 PR降低了DC在乳腺中的募集和功能，从而促进免疫选择随后的乳腺肿瘤的发育和生长。以下特定目的：1）定义P4处理和PR Express影响DC的机制招募鼠乳腺和PR+乳腺肿瘤； 2 从P4处理的PR+乳腺肿瘤中分离出的DC的活性状态； P4介导的直流抑制乳腺肿瘤生长的贡献。细胞RNA测序（SCRNA-SEQ）确定P4是否影响参与DC的细胞因子的释放在AIM 2中募集到乳腺肿瘤细胞。使用合元肿瘤模型的肿瘤浸润DC的功能，其中标记将通过 SCRNA-seq，流式细胞率和T细胞泛滥分析。确定DCS的耗竭是否会影响P4对乳腺肿瘤的生长促进作用。成功地完成了支撑工作的工作，沃尔为免疫耐受机制提供了新颖促进乳腺癌的发育和生长。 P4/PR信号用抗蛋白毒素促进直流功能并增强免疫介导的消除肿瘤细胞。