Matrix density promotes pro-tumorigenic hormone actions in breast cancer

摘要 尽管许多雌激素受体阳性(ER+)的女性原发癌症成功 接受手术和辅助抗雌激素治疗，转移治疗耐药ER+ 癌症占乳腺癌相关死亡的大部分。对科学发展观的新认识 开发新的方法需要作为疾病过程基础的生物学。在这次更新中 应用程序，我们建立在我们之前的发现基础上，展示了 雌激素和细胞外基质(ECM)在两者微环境中的特征 原发肿瘤和转移的生态位，增加了肺转移的负担。我们展示了 这种雌激素重塑了原发肿瘤的ECM结构，使胶原纤维和 与更具侵袭性的癌症相关的ECM成分合成增加，并发生改变 肺转移灶中的细胞外基质成分。此外，我们发现这种胶原蛋白排列 患者肿瘤中的信号与炎症标志物相关，包括COX-2和CD163+ 巨噬细胞，预后差。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)/癌症相关的协同作用 成纤维细胞(CAF)和巨噬细胞/炎症，为原发和转移肿瘤提供燃料 攻击性。我们将利用我们强大的体内免疫活性的转移性ER+乳腺模型 癌症、体外系统、PDX模型和临床患者样本在 遵循目标。目的1：确定ER+乳腺癌转移进展的步骤 被肿瘤细胞和其他雌激素靶标中的雌激素活性所改变。目标2：确定 雌激素对CAF的作用如何改变间质ECM以介导肿瘤进展，确定 介导这一作用的受体，并从天然基质基质中识别ECM信号 来自ER+浸润性导管癌活检组织，指示雌激素对肿瘤细胞生长的作用 和迁徙。目标3：确定雌激素如何影响免疫转移介质，包括 巨噬细胞活性与炎性肿瘤微环境。目标4：评估员工的能力 逆转E2促进的转移和转移后步骤的标准护理治疗方法 治疗雌激素再暴露促进肺部残留病变生长，并审问 雌激素改变的ECM结构与巨噬细胞活动/炎症的相互关系。 我们的研究将阐明雌激素在播散和肺转移中的作用。 ER+乳腺的定植与治疗、转移休眠和复发的关系 癌症，并揭示潜在的干预地点。

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.