NSAIDs During Postpartum Involution for Breast Cancer Chemoprevention

项目摘要：虽然以前没有人认识到，但现在有记录表明，在 10年是早发性乳腺癌和不良预后的独立预测因素。这些癌症，基于 主要基于我们实验室的研究，现在被称为产后乳腺癌(PPBC)，代表着一种 严重的临床问题。仅在美国，每年就有约15,000名年轻女性(占所有女性的约50% 年轻女性的乳腺癌病例)是在产后高危时期确诊的。在我们的研究中 Lab提出了一种假说，即断奶引起的乳腺退化是增加的驱动因素 PPBC患者的发病率和转移。在断奶诱导退缩的短暂窗口期间， 正常退缩的乳腺偏向于有利于肿瘤的微环境，因为它表现出增加。 淋巴管生成、成纤维细胞激活和细胞外基质沉积；以及对髓系细胞的浓缩 衍生抑制细胞(MDSC)、M2偏斜的巨噬细胞以及Th-17、Th-2和Treg偏斜的T细胞 与未分娩的腺体相比。这些发现支持我们的假设，即亚临床的、非生命的 在断奶诱导的退化过程中，威胁疾病进展为明显的浸润性癌症。在多个 小鼠模型，我们证实退化腺的组织微环境增加了乳腺肿瘤 发病率和进展性。此外，我们还证明了布洛芬(IBU)治疗的靶点是消退。 窗块&GT；50%的这些肿瘤是从新出现的，取决于模型。此外，在那些能够 一旦出现，转移性疾病的进展就会受到抑制。IBU似乎通过一种机制抑制 PPBC是通过抗肿瘤免疫，随着IBU增加细胞毒性T细胞的数量，与 加强免疫监控。重要的是，我们发现IBU有能力恢复 免疫系统在没有不良宿主自身免疫反应的情况下发生，并不影响能力 为了在以后的怀孕中成功地哺育他们的孩子。这些发现支持临床应用。 IBU参与了一项建设和平委员会预防试验。我们的研究还确定了提高疗效的机会，以及 维生素D(VitD)是基于其抗肿瘤和抗炎活性而提出的，其安全性和安全性 尤其与产后妇女有关，她们是维生素D缺乏症的高危人群。在这里，我们建议1) 探讨IBU联合维生素D治疗PPBC动物模型的疗效 改善人类相关性，2)确定IBU+/-VitD减轻促肿瘤形成的机制 退化腺体的微环境，目的是确定更多的退化特异靶标；以及 3)将我们对啮齿类动物的研究定义为“处于危险中”的退化乳腺的免疫成分 女性，通过定义正常人类乳房中不同生殖状态的免疫环境。仅限直通 了解正常的、退化的人类乳房是如何增加BRCA风险的，我们能否识别出 目标是提高我们的化学预防策略的有效性，为预防PPBC奠定基础。

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.