Cancer-associated fibroblasts in estrogen receptor positive breast cancer.

 描述（由申请人提供）：乳腺癌的上皮成分显示出显著水平的细胞异质性。这种现象可以通过管腔型乳腺癌（最常见的乳腺癌亚型）中雌激素受体（ER）表达的变化来最好地可视化。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，即使在复发或转移性疾病的患者中，ER仍然是一个关键的治疗靶点。尽管ER的临床重要性，但仍不清楚个体肿瘤如何维持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异性的，以及是否可以影响它以有利于更好的治疗反应，这将具有很大的临床用途。迄今为止，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鉴定了两种癌症相关成纤维细胞（CAF）亚型，其由CD 146表达定义。CAF亚型在其基因表达谱、其对肿瘤细胞中ER表达的影响以及其指导对抗内分泌治疗的反应的能力方面不同。 基于我们的初步数据，我们假设CD 146阳性和阴性CAF通过Notch、ErbB和Ephrin受体家族成员的信号传导差异性地修饰乳腺癌细胞中的ER表达，并且对肿瘤对治疗的反应具有关键作用。为了验证这一假设，我们将使用将我们的基因和功能定义的原代人乳腺CAF与乳腺癌细胞系和我们建立的ER+乳腺癌患者源性异种移植（PDX）模型相结合的方法。在具体目标1中，我们将定义负责乳腺癌细胞中ER表达和对雌激素反应的CD 146 CAF亚型定向变化的机制。具体目标2将确定肿瘤-CAF串扰对抗内分泌抗性发展的影响。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中抗内分泌治疗反应的影响。拟定的研究将增强我们对管腔型、ER+乳腺癌治疗耐药性的理解。我们的最终目标是确定靶向肿瘤-间质相互作用的方法，降低疾病复发的风险，改善乳腺癌患者的预后。

 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.