Matrix density promotes pro-tumorigenc hormone actions in breast cancer

基质密度促进乳腺癌中促肿瘤激素的作用

• 批准号: 9228974
• 负责人: LINDA A. SCHULER
• 金额: $ 46.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228974
• 关键词: Address; Aggressive behavior; Animals; Automobile Driving; Behavior; Breast; Breast Cancer Cell; Breast Carcinoma; Carcinoma; Cell Proliferation; Clinical; Collagen; Collagen Fiber; Data; Deposition; Development; Disease Progression; Environment; Equilibrium; Estrogen Antagonists; Estrogen Receptors; Estrogen Therapy; Estrogen receptor positive; Estrogens; Extracellular Matrix; Fibroblasts; Fibronectins; Goals; Hormonal; Hormone Receptor; Hormones; Human; Immunocompetent; In Vitro; Incidence; Lead; MAPK3 gene; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mammographic Density; Mechanics; Mediator of activation protein; Modeling; Neoplasm Metastasis; Outcome; Pathology; Pathway interactions; Patients; Phosphorylation; Process; Production; Prolactin; Prolactin Receptor; Publishing; Regulation; Resistance; Risk Factors; Role; Sampling; Signal Pathway; Signal Transduction; Stat5 protein; Stromal Cells; Structure; System; Therapeutic; Tissue Microarray; Tumorigenicity; Woman; Xenograft Model; Xenograft procedure; base; behavioral outcome; breast density; cell behavior; density; extracellular; feeding; high risk; in vivo; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; overexpression; polyacrylamide; prognostic signature; public health relevance; therapy resistant; three dimensional cell culture; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Increased mammographic density is associated with increased incidence of breast cancer, and is largely attributed to increased levels of stromal collagen and changes in the composition of the extracellular matrix. These changes result in a stroma that is mechanically stiffened, triggering signaling pathways that lead to tumor development, invasion and metastasis. In addition, we find that aligned collagen fibers facilitate invasion, correlate with metastasis, and serve as a prognostic signature for poor outcome in patients. While hormones, including prolactin and estrogen, have been associated with elevated mammographic density in patients and are independently associated with the development of estrogen receptor positive (ER�+) breast cancer, little is known about the interplay of hormones and extracellular matrix composition and organization in the development, progression and therapeutic resistance of breast cancer. Moreover, although prolactin exposure is associated with higher risk of metastases and poor long term survival of ER�+ cancers, the best studied prolactin-activated mediator, STAT5, is associated with anti-estrogen sensitivity and better differentiated tumors. Our preliminary data demonstrate that elevated collagen density alone can shift the spectrum of PRL-induced signals away from STAT5 and toward ERK1/2, which is associated with pro-proliferation/invasion signals, and reduces estrogen responsiveness. Based on these findings, in this revised proposal, we will address the hypothesis that changes in the density, composition, and alignment of the ECM switch the balance of hormonal signals from pro-differentiation to pro-tumorigenic, which further alters the stroma in a feed-forward manner to promote breast cancer progression. In Aim 1, we will utilize a defined 3D culture system, mechanically precise collagen-coated polyacrylamide substrata, and aligned collagen matrices to examine effects in hormonally responsive breast carcinoma cells on prolactin and estrogen-induced signals and behavioral outcomes. In Aim 2, we will examine the interplay between carcinoma-associated fibroblasts, normal mammary fibroblasts, hormones and tumor cells in vitro. In Aim 3, we will extend these studies in vivo, examining these interactions on disease progression, metastasis and responsiveness to anti-estrogen therapy in xenograft models, immunocompetent mouse models and clinical tumors. Although many ER�+ cancers are successfully treated by anti-estrogen therapies, nearly 25% display initial or acquired resistance and thereby constitute the majority of breast cancer mortality. Understanding the interactions of the extracellular environment on hormonal signals will illuminate the contribution of these factors to breast pathology and therapeutic responsiveness, and point to novel treatment opportunities.

描述（由申请人提供）：乳腺摄影密度增加与乳腺癌发病率增加相关，主要归因于基质胶原蛋白水平增加和细胞外基质组成变化。这些变化导致基质机械硬化，触发导致肿瘤发展、侵袭和转移的信号通路。此外，我们发现排列整齐的胶原纤维促进侵袭，与转移相关，并作为患者预后不良的预后标志。虽然激素，包括催乳素和雌激素，与患者乳腺摄影密度升高相关，并与雌激素受体阳性（ER+）乳腺癌的发展独立相关，但对激素和细胞外基质组成和组织的相互作用知之甚少乳腺癌的发展，进展和治疗抗性。此外，尽管催乳素暴露与ER+癌症的转移风险较高和长期生存率较低相关，但研究得最好的催乳素激活介质STAT 5与抗雌激素敏感性和更好的分化肿瘤相关。我们的初步数据表明，单独升高的胶原蛋白密度可以将PRL诱导的信号谱从STAT 5向ERK 1/2转移，ERK 1/2与促增殖/侵袭信号相关，并降低雌激素反应性。 基于这些发现，在这个修订后的提案中，我们将解决这样一个假设，即ECM的密度、组成和排列的变化将激素信号的平衡从促分化切换到促肿瘤发生，从而以前馈方式进一步改变基质以促进乳腺癌进展。在目标1中，我们将利用一个定义的三维培养系统，机械精确的胶原蛋白包被的聚丙烯酰胺基质，和对齐的胶原蛋白基质，以检查在泌乳素和雌激素诱导的信号和行为结果的乳腺癌细胞的反应。在目标2中，我们将在体外研究癌相关成纤维细胞、正常乳腺成纤维细胞、激素和肿瘤细胞之间的相互作用。在目标3中，我们将在体内扩展这些研究，在异种移植模型、免疫活性小鼠模型和临床肿瘤中检查这些相互作用对疾病进展、转移和抗雌激素治疗的反应性。 尽管许多ER+癌症通过抗雌激素疗法得到成功治疗，但近25%的患者表现出初始或获得性耐药，从而构成了乳腺癌死亡率的大部分。了解细胞外环境对激素信号的相互作用将阐明这些因素对乳腺病理学和治疗反应性的贡献，并指出新的治疗机会。