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: 8973155
• 负责人: Patricia J Keely
• 金额: $ 3.63万
• 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/8973155
• 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; Health; Hormonal; Hormone Receptor; Hormones; Human; Immunocompetent; In Vitro; Incidence; Lead; MAPK3 gene; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mammographic Density; Mediator of activation protein; Modeling; Mus; Neoplasm Metastasis; Outcome; Pathology; Pathway interactions; Patients; Phosphorylation; Process; Production; Prolactin; Publishing; Regulation; Resistance; Risk Factors; Role; Sampling; Signal Pathway; Signal Transduction; Stat5 protein; Stromal Cells; Structure; System; Therapeutic; Tissue Microarray; Woman; Xenograft Model; Xenograft procedure; base; behavioral outcome; breast density; cell behavior; density; extracellular; feeding; high risk; hormone therapy; in vivo; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; overexpression; polyacrylamide; prognostic; therapy resistant; 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（由适用提供）：乳房X线摄影密度的增加与乳腺癌的发病率增加有关，主要归因于基质胶原蛋白水平的增加以及细胞外基质组成的变化。这些变化导致基质机械僵硬，从而触发信号通路，从而导致肿瘤发育，侵袭和转移。此外，我们发现制备入侵的胶原纤维对齐胶原纤维，与转移相关，并作为患者预后不良的预后签名。尽管包括催乳素和雌激素在内的马与患者的乳房X线摄影密度升高有关，并且与雌激素受体阳性（ER？+）乳腺癌的发展独立相关，但对马匹的相互作用和细胞外基质组成和在发育，进展，进展，进展和乳腺癌的治疗性抗性中的相互作用知之甚少。此外，尽管催乳素的暴露与较高的转移风险和ER¿ +癌症的长期生存率较差有关，但最好的研究菌蛋白激活的介质STAT5与抗雌激素敏感性和更好的分化肿瘤有关。我们的初步数据表明，仅升高的胶原密度可以将PRL诱导的信号从STAT5转移到ERK1/2，这与促增殖/入侵信号有关，并降低雌激素反应性。基于这些发现，在这项修订后的提案中，我们将解决以下假设：ECM的密度，组成和对齐的变化转换了从促分化到亲肿瘤的平衡，从而进一步改变了基质，从而改变了基质，从而以饲料前向方式改变了乳腺癌的进展。在AIM 1中，我们将利用定义的3D培养系统，机械精确的胶原蛋白涂层的聚丙烯酰胺基质，并对齐胶原蛋白材料来检查激素反应式抗乳腺癌细胞对催乳素和雌激素诱导的信号和行为抗性的影响。在AIM 2中，我们将在体外检查癌相关成纤维细胞，正常乳腺成纤维细胞，激素和肿瘤细胞之间的相互作用。在AIM 3中，我们将在体内扩展这些研究，研究异种移植模型，免疫能力小鼠模型和临床肿瘤中有关疾病进展，转移和对抗雌激素治疗的反应的这些相互作用。尽管许多ER¿ +癌症通过抗雌激素疗法成功治疗，但几乎25％的初始抗药性表现出最初或获得的抗药性，因此构成了大多数乳腺癌死亡率。了解细胞外环境在激素信号上的相互作用将阐明这些因素对乳房病理和治疗反应的贡献，并指向新的治疗机会。