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（由申请人提供）：乳房X线照相密度的增加与乳腺癌发病率的增加相关，并且很大程度上归因于基质胶原水平的增加和细胞外基质的组成的变化。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标志。虽然激素（包括催乳素和雌激素）与患者乳房 X 光密度升高有关，并且与雌激素受体阳性 (ER¿+) 乳腺癌的发展独立相关，但人们对激素与细胞外基质组成和组织在乳腺癌发生、进展和治疗耐药中的相互作用知之甚少。此外，尽管催乳素暴露与较高的转移风险和 ER¿+癌症的长期生存不良相关，但研究最充分的催乳素激活介质 STAT5 与抗雌激素敏感性和更好分化的肿瘤相关。我们的初步数据表明，仅提高胶原蛋白密度就可以将 PRL 诱导的信号谱从 STAT5 转移到 ERK1/2（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，我们将提出这样的假设：ECM 的密度、组成和排列的变化将激素信号的平衡从促分化转变为促肿瘤发生，这进一步以前馈方式改变基质，促进乳腺癌进展。在目标 1 中，我们将利用明确的 3D 培养系统、机械精确的胶原包被聚丙烯酰胺基质和对齐的胶原基质来检查激素反应性乳腺癌细胞对催乳素和雌激素诱导的信号和行为结果的影响。在目标 2 中，我们将在体外检查癌症相关成纤维细胞、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、转移和对抗雌激素治疗的反应。 尽管许多 ER¿+ 癌症可以通过抗雌激素疗法成功治疗，但近 25% 的癌症表现出初始或获得性耐药性，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和治疗反应的贡献，并指出新的治疗机会。