Cancer-associated fibroblasts in estrogen receptor positive breast cancer.

雌激素受体阳性乳腺癌中的癌症相关成纤维细胞。

• 批准号: 9082027
• 负责人: Peter Kabos
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9082027
• 关键词: Base Composition; Base Ratios; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer Etiology; Cell Line; Cells; Cessation of life; Clinical; Clonal Evolution; Colorado; DTR gene; Data; Development; Disease; ESR1 gene; Endocrine; Eph Family Receptors; Ephrins; Epigenetic Process; Epithelial; Equilibrium; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; Estrogens; Family; Feedback; Fibroblasts; Gene Expression; Gene Expression Profile; Genetic; Genomics; Goals; Growth; Heterogeneity; Human; Individual; Intrinsic factor; Link; MCAM gene; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mitogens; Modeling; Modification; Molecular Profiling; Mutation; Neuregulins; Normal tissue morphology; Outcome; Paracrine Communication; Pathway interactions; Patients; Phenotype; Prevalence; Receptor Gene; Recurrence; Regulation; Regulatory Element; Resistance; Resistance development; Role; Sampling; Signal Pathway; Signal Transduction; Surface; Testing; Therapeutic; Treatment Failure; Universities; Variant; Woman; Xenograft Model; Xenograft procedure; base; cancer cell; cancer stem cell; cancer subtypes; clinical application; clinical biomarkers; cohort; disorder risk; drug development; genetic signature; hormone therapy; human disease; improved; improved outcome; insight; malignant breast neoplasm; member; neoplastic cell; notch protein; novel; novel diagnostics; novel therapeutics; personalized care; prognostic; promoter; public health relevance; receptor expression; research and development; response; therapeutic target; therapy resistant; tool; trait; treatment response; tumor; tumor heterogeneity; tumor microenvironment; tumor xenograft

 DESCRIPTION (provided by applicant): The epithelial component of breast cancers shows a remarkable level of cellular heterogeneity. This phenomenon can be best visualized by the variations of estrogen receptor (ER) expression in luminal breast cancer, which is the most common breast cancer subtype. Clinically, only 1% of ER positive cells are sufficient to justify the use of anti-endocrine therapy. In addition, ER remains a crucial therapeutic target even in patients who develop recurrent or metastatic disease. Despite the clinical importance of ER, it remains unclear how individual tumors maintain a balance of ER positive and negative cells. It would be of great clinical use to define whether this phenomenon is host or disease specific, and if it can be influenced to favor a better treatment response. To date, most research and drug development efforts have focused on intrinsic factors leading to cellular heterogeneity in ER+ breast cancer. However, our data support a profound and rapid effect of the tumor microenvironment on ER expression in tumor cells. We have identified two subtypes of cancer- associated fibroblasts (CAFs) within breast cancer stroma, which are defined by CD146 expression. The CAF subtypes differ in their gene expression profiles, their influence on ER expression in tumor cells, and their ability to direct the response to anti-endocrine therapy. Based on our preliminary data we hypothesize that CD146 positive and negative CAFs differentially modify ER expression in breast cancer cells by signaling through members of Notch, ErbB and Ephrin receptor families and have a critical effect on tumor response to treatment. To test this hypothesis, we will use approaches that combine our genetically and functionally defined primary human breast CAFs with breast cancer cell lines and our established patient-derived xenograft (PDX) models of ER+ breast cancer. In Specific Aim 1, we will define the mechanism responsible for CD146 CAF subtype-directed changes in ER expression and response to estrogen in breast cancer cells. Specific aim 2 will determine the influence of tumor-CAF crosstalk on development of anti-endocrine resistance. In specific aim 3, we will assess fibroblast subtypes in cancer and normal breast tissue, and their influence on response to anti-endocrine therapy in patient samples. The proposed studies will enhance our understanding of treatment resistance of luminal, ER+ breast cancer. Our ultimate goal is to identify approaches to target the tumor-stroma interactions, reduce the risk of disease recurrence and improve outcomes for patients with breast cancer.

 描述(申请人提供)：乳腺癌的上皮成分显示出显著的细胞异质性。在最常见的乳腺癌亚型--管腔型乳腺癌中，雌激素受体(ER)表达的变化最能直观地反映这一现象。临床上，只有1%的ER阳性细胞足以证明使用抗内分泌治疗是合理的。此外，ER仍然是一个重要的治疗靶点，即使在发生复发或转移性疾病的患者中也是如此。尽管ER具有重要的临床意义，但目前尚不清楚单个肿瘤如何维持ER阳性和阴性细胞的平衡。确定这种现象是否是宿主或疾病特有的，以及是否可以影响它以利于更好的治疗反应，这将是非常有临床意义的。到目前为止，大多数研究和药物开发工作都集中在导致ER+乳腺癌细胞异质性的内在因素上。然而，我们的数据支持肿瘤微环境对肿瘤细胞中ER表达的深刻而快速的影响。我们已经在乳腺癌间质中发现了两种癌症相关成纤维细胞(CAF)亚型，它们由CD146的表达来定义。不同的CAF亚型在基因表达谱、对肿瘤细胞ER表达的影响以及指导抗内分泌治疗反应的能力上存在差异。根据我们的初步数据，我们假设CD146阳性和阴性CAF通过Notch、ErbB和EPhin受体家族成员的信号差异地改变乳腺癌细胞中ER的表达，并在肿瘤治疗反应中发挥关键作用。为了验证这一假设，我们将使用将我们从基因和功能上定义的原代人类乳腺CAF与乳腺癌细胞株和我们建立的ER+乳腺癌患者来源异种移植(PDX)模型相结合的方法。在特定的目标1中，我们将确定CD146 CAF亚型导致乳腺癌细胞ER表达和对雌激素反应的改变的机制。特异靶2将确定肿瘤-CAF串扰对抗内分泌耐药发展的影响。在具体目标3中，我们将评估癌症和正常乳腺组织中的成纤维细胞亚型，以及它们对患者样本抗内分泌治疗反应的影响。建议的研究将增强我们对腔内ER+乳腺癌治疗耐药的理解。我们的最终目标是找到针对肿瘤-间质相互作用的方法，降低疾病复发的风险，并改善乳腺癌患者的预后。