NSAIDs During Postpartum Involution for Breast Cancer Chemoprevention

产后复健期间使用非甾体抗炎药进行乳腺癌化学预防

• 批准号: 10372923
• 负责人: Pepper J Schedin
• 金额: $ 37.92万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372923
• 关键词: Accounting; Age; Anti-Inflammatory Agents; Autoimmune; Biology; Breast; Breast Epithelial Cells; CD8-Positive T-Lymphocytes; Cell Death; Characteristics; Chemoprevention; Child; Clinical; Collection; Cytotoxic T-Lymphocytes; Data; Deposition; Diagnosis; Disease; Event; Exhibits; Extracellular Matrix; Fibroblasts; Foundations; Functional disorder; Gland; Goals; High Risk Woman; Hot Spot; Human; ITGAM gene; Ibuprofen; Immune; Immune Tolerance; Immune system; Immunologic Surveillance; Incidence; Inflammatory; Intervention; Lactation; Life; Lymphangiogenesis; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Metastatic breast cancer; Metastatic to; Modeling; Myeloid-derived suppressor cells; Neoplasm Metastasis; Neoplasm Transplantation; Non-Steroidal Anti-Inflammatory Agents; Noninfiltrating Intraductal Carcinoma; Nulliparity; Nurses; Outcome; Pathway interactions; Patients; Phenotype; Physiological; Play; Postpartum Period; Postpartum Women; Pregnancy; Prevention; Prevention strategy; Prevention trial; Preventive; Process; Prognosis; Reaction; Regulatory T-Lymphocyte; Research; Risk; Rodent; Rodent Model; Role; Safety; Secondary Cancer Prevention; Secondary Prevention; T-Lymphocyte; Testing; Time; TimeLine; Tissues; Translating; Tumor Immunity; Tumor-infiltrating immune cells; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Weaning; Woman; Work; anticancer activity; arm; base; breast cancer diagnosis; cancer chemoprevention; cancer invasiveness; cost; early onset; high risk; immunoregulation; improved; improved outcome; macrophage; malignant breast neoplasm; mammary epithelium; mouse model; novel; pill; postnatal; postpartum breast cancer; pre-clinical; pregnant; prevent; programs; protective effect; reproductive; safety and feasibility; transplant model; tumor; tumorigenic; volunteer; wound healing; young woman

Project Summary: While previously unrecognized, it is now documented that having delivered a child within 10 years is an independent predictor of early onset breast cancer and poor outcomes. These cancers, based largely on work from our labs, is now referred to as postpartum breast cancer (PPBC), and represents a significant clinical problem. Every year in the US alone, ~15,000 young women (accounting for ~50% of all young women’s breast cancer cases) are diagnosed during the high risk, postpartum period. Research in our lab has advanced the hypothesis that weaning-induced mammary gland involution is the driver of increased incidence and metastasis in PPBC patients. During the transitory window of weaning-induced involution, the normal involuting mammary gland is skewed towards a pro-tumor microenvironment, as it exhibits increased lymphangiogenesis, fibroblast activation, and extracellular matrix deposition; as well as enrichment for myeloid derived suppressor cells (MDSC), M2-skewed macrophages, and Th-17, Th-2 and Treg skewed T cells compared to nulliparous glands. These discoveries support our hypothesis that sub-clinical, non-life threatening disease progresses to overtly invasive cancer during weaning-induced involution. In multiple murine models, we confirm that the tissue microenvironment of the involuting gland increases mammary tumor incidence and progression. Further, we demonstrate that ibuprofen (IBU) treatment targeted to the involution window blocks >50% of these tumors from emerging, depending on model. Further, of those tumors that do emerge, progression to metastatic disease is suppressed. One mechanism by which IBU appears to inhibit PPBC is through anti-tumor immunity, as IBU increases the number of cytotoxic T cells, consistent with increased immune surveillance. Importantly, we find the ability of IBU to restore the adaptive arm of the immune system occurs in the absence of adverse host autoimmune reactions and does not impact the ability of dams to successfully nurse their young in subsequent pregnancies. These findings support clinical utility of IBU in the setting of a PPBC prevention trial. Our studies also identify opportunities to improve efficacy, and vitamin D (Vit D) is proposed based on its anti-tumor and anti-inflammatory activity, and its safety and particular relevance in postpartum women, who are at high risk for VitD deficiency. Here we propose to 1) investigate the efficacy of IBU treatment in combination with vitamin D, in rodent models of PPBC with improved human relevance, 2) identify the mechanism by which IBU +/- VitD mitigates the pro-tumorigenic microenvironment of the involuting gland with the goal of identifying additional involution-specific targets; and 3) translate our rodent studies defining the ‘immune composition of the “at risk” involuting mammary gland to women, by defining the immune milieu in the normal human breast across reproductive states. Only through understanding how the normal, involuting human breast confers increased BrCa risk, can we identify additional targets to improve the efficacy of our chemoprevention strategy and lay the foundation for PPBC prevention.

项目摘要：虽然以前未被承认，但现在有记录显示，在 10 年是早发乳腺癌和不良预后的独立预测因子。这些癌症，基于 主要是我们实验室的工作成果，现在被称为产后乳腺癌 (PPBC)，代表了 重大临床问题。仅在美国，每年就有约 15,000 名年轻女性（约占全部女性的 50%） 年轻女性乳腺癌病例）是在高风险产后时期被诊断出来的。我们的研究 实验室提出了这样的假设：断奶引起的乳腺退化是乳腺退化增加的驱动因素。 PPBC 患者的发病率和转移。在断奶引起的复旧的短暂窗口期间， 正常的退化乳腺偏向于促肿瘤微环境，因为它表现出增加的 淋巴管生成、成纤维细胞激活和细胞外基质沉积；以及骨髓细胞的富集 衍生抑制细胞 (MDSC)、M2 偏向巨噬细胞以及 Th-17、Th-2 和 Treg 偏向 T 细胞 与未产卵的腺体相比。这些发现支持了我们的假设，即亚临床、非生命 在断奶诱导的退化过程中，威胁性疾病会发展为明显的侵袭性癌症。在多个 在小鼠模型中，我们证实退化腺体的组织微环境会增加乳腺肿瘤 发病率和进展。此外，我们证明布洛芬 (IBU) 治疗针对的是复旧 根据模型的不同，窗口可阻止超过 50% 的肿瘤出现。此外，在那些肿瘤中 出现后，转移性疾病的进展受到抑制。 IBU 似乎抑制的一种机制 PPBC 是通过抗肿瘤免疫，因为 IBU 增加了细胞毒性 T 细胞的数量，这与 增强免疫监视。重要的是，我们发现 IBU 能够恢复自适应臂 免疫系统在没有不良宿主自身免疫反应的情况下发生，并且不会影响能力 的母鼠在随后的怀孕中成功地哺育幼崽。这些发现支持了临床实用性 IBU 在 PPBC 预防试验中的应用。我们的研究还发现了提高功效的机会，以及 维生素D（Vit D）是基于其抗肿瘤和抗炎活性及其安全性和有效性而被提出的。 对于维生素D缺乏症高风险的产后妇女尤其重要。在这里我们建议1) 研究 IBU 与维生素 D 联合治疗在 PPBC 啮齿动物模型中的疗效 提高人类相关性，2) 确定 IBU +/- VitD 减轻促肿瘤发生的机制 退化腺体的微环境，目的是确定额外的退化特定目标；和 3）将我们的啮齿动物研究定义为“处于危险中”的乳腺免疫成分 女性，通过定义不同生育状态下正常人类乳房的免疫环境。只有通过 了解正常的、退化的人类乳房如何增加 BrCa 风险后，我们能否识别出额外的 目标是提高化学预防策略的有效性，为 PPBC 的预防奠定基础。