Matrix density promotes pro-tumorigenic hormone actions in breast cancer

摘要 虽然许多雌激素受体阳性（ER+）原发性癌症的女性成功地 接受手术和辅助抗雌激素治疗，转移性耐药ER+ 癌症占乳腺癌相关死亡的大多数。新认识 疾病过程的生物学基础需要开发新的方法。在这次更新中， 应用程序，我们建立在我们以前的研究结果表明动态互惠之间 雌激素和细胞外基质（ECM）的特点，在微环境中的两个 原发性肿瘤和转移性小生境，其加重了肺转移负荷。我们展示 雌激素重塑原发肿瘤的ECM结构，排列胶原纤维， 增加与更具侵袭性的癌症相关的ECM成分的合成， 肺转移灶中的ECM成分。此外，我们发现这种胶原蛋白排列 患者肿瘤中的特征与炎症标志物相关，包括考克斯-2和CD 163 + 巨噬细胞和预后不良。在目前的提案中，我们假设雌激素 协调ER+肿瘤细胞、细胞外基质（ECM）/癌症相关细胞之间的协同作用。 成纤维细胞（CAF）和巨噬细胞/炎症，以促进原发性和转移性肿瘤 侵略我们将利用我们强大的转移性ER+乳腺癌的免疫活性体内模型， 癌症，体外系统，PDX模型和临床患者样本，以测试这一假设， 的目标。目的1：确定ER+乳腺癌转移进展的步骤， 被肿瘤细胞中的雌激素活性以及其他雌激素靶点改变。目标2：确定 雌激素对CAFs的作用如何改变基质ECM以介导肿瘤进展， 介导这种作用的受体，并从天然基质基质中鉴定ECM特征 来自ER+浸润性导管癌活检，指示雌激素对肿瘤细胞生长的作用 和移民。目的3：确定雌激素如何影响免疫转移介质，包括 巨噬细胞活性和炎性肿瘤微环境。目标4：评估能力 逆转E2促进的转移步骤和后转移的标准治疗方法 治疗雌激素再暴露，以促进残留肺部病变的生长，并询问 E2改变的ECM结构和巨噬细胞活性/炎症之间的相互关系。 我们的研究将阐明雌激素在播散和肺转移中的作用 定植，对ER+乳腺癌的治疗、转移性休眠和复发的影响 癌症，并揭示潜在的干预位点。

ABSTRACT Although many women with estrogen receptor positive (ER+) primary cancers are successfully treated with surgery and adjuvant anti-estrogen therapies, metastatic therapy-resistant ER+ cancers account for the majority of breast cancer related deaths. New understanding of the biology underlying disease processes is required to develop new approaches. In this renewal application, we build on our previous findings demonstrating dynamic reciprocity between estrogen and features of the extracellular matrix (ECM) in the microenvironments of both the primary tumor and the metastatic niche which fuel the pulmonary metastatic burden. We showed that estrogen remodels the ECM architecture of the primary tumor, aligning collagen fibers and increasing synthesis of ECM components associated with more aggressive cancers, and alters ECM components in the lung metastatic niche. Moreover, we showed that this collagen alignment signature in patient tumors correlates with inflammatory markers, including COX-2 and CD163+ macrophages, and poor prognosis. In the current proposal, we hypothesize that estrogen orchestrates synergy among ER+ tumor cells, the extracellular matrix (ECM)/ cancer associated fibroblasts (CAFs), and macrophages/ inflammation, to fuel primary and metastatic tumor aggression. We will utilize our robust immunocompetent in vivo model of metastatic ER+ breast cancer, in vitro systems, PDX models and clinical patient samples to test this hypothesis in the following aims. Aim 1: Identify the steps in metastatic progression of ER+ breast cancer which are altered by estrogen activity in tumor cells as well as other estrogen targets. Aim 2: Determine how estrogen action on CAFs modifies the stromal ECM to mediate tumor progression, determine the receptors that mediate this action, and identify ECM signatures from native stromal matrix from ER+ invasive ductal carcinoma biopsies that instruct estrogen action on tumor cell growth and migration. Aim 3: Determine how estrogen impacts immune metastatic mediators, including macrophage activity and the inflammatory tumor microenvironment. Aim 4: Evaluate the ability of standard of care therapeutic approaches to reverse E2-promoted steps in metastasis and post- treatment estrogen re-exposure to promote growth of residual pulmonary lesions, and interrogate the interrelationships among E2-altered ECM structure, and macrophage activity/inflammation. Our studies will illuminate the role of estrogen in dissemination and pulmonary metastatic colonization, with implications for therapy, metastatic dormancy and recurrence of ER+ breast cancer, and reveal potential sites for intervention.