Evaluating How Fluid Shear Stress Alters Estrogen Receptor Phenotype in Metastatic Breast Cancer

评估流体剪切应力如何改变转移性乳腺癌中的雌激素受体表型

• 批准号: 10290790
• 负责人: Elizabeth Martin
• 金额: $ 7.01万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10290790
• 关键词: Address; Biological Adaptation; Breast Cancer Cell; Breast Cancer Patient; Cancer cell line; Cell Line; Cell Survival; Cells; Cellular Stress; ChIP-on-chip; Chemoresistance; Clinical; Coupled; Data; Development; Drug Targeting; Drug resistance; Endocrine; Engineering; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogen receptor positive; Estrogens; Evaluation; Exhibits; Exposure to; Foundations; Fulvestrant; Gene Expression; Genotype; Growth Factor; In Situ; Individual; Lead; Liquid substance; MCF7 cell; Mediating; Metastatic breast cancer; Microfluidics; Microscopy; Modeling; Mutation; Nature; Neoplasm Metastasis; Oncology; Outcome; Output; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Population; Primary Neoplasm; Proteins; Quantitative Reverse Transcriptase PCR; Regulation; Research; Resistance; Role; Signal Transduction; Site; Stress; Technology; Testing; Time; Travel; United States National Institutes of Health; Work; base; cancer cell; epithelial to mesenchymal transition; experience; experimental study; hormone therapy; individual response; insight; malignant breast neoplasm; mortality; new therapeutic target; novel; novel therapeutics; receptor expression; response; shear stress; single cell analysis; therapy design

PROJECT SUMMARY Approximately 70% of breast cancer patients will present with an estrogen receptor positive (ER+) subtype. Of these patients, most will initially respond to endocrine therapy when treating the primary tumor. Unfortunately, following metastatic spread, many of these patients develop a resistance to endocrine therapies which results in a significant increase in patient mortality because there is no viable treatment for metastatic breast cancer. Following metastasis, the current median survival time is ~5-10 years, which reinforces the critical need to better understand the cellular mechanisms leading to endocrine therapy resistance in metastatic tumors. Endocrine resistance at metastatic sites is hypothesized to occur through multiple mechanisms including: (i) loss of the estrogen receptor, (ii) acquisition of additional mutations, and/or (iii) alterations in estrogen and growth factor mediated signaling cascades. During metastasis, ER+ breast cancer cells are exposed to high magnitudes of fluid shear stress (FSS) (up to 60 dyn/cm2) and fluid-induced deformation while traveling through the vasculature. Prior work has identified that FSS induces an increased activation of kinase pathways, including those involved in rapid estrogen signaling and associated endocrine resistance in cancer cell lines. Unfortunately, the role for FSS on the regulation of ER signaling and the biological adaptation of ER+ breast cancer during metastasis is not fully understood. To elucidate how FSS drives endocrine response in metastatic breast cancer, we propose the following hypothesis: Exposure of ER+ breast cancer cells to FSS represses ER expression and induces activation of growth factor signaling cascades and subsequent endocrine resistance. We propose to test this hypothesis utilizing a modular microfluidic platform capable of exposing breast cancer cells to well-controlled, uniform magnitudes and durations of FSS that mimics in situ conditions that occur during metastatic spread. Specifically, we will (1) Determine how FSS alters estrogen receptor expression and growth factor pathways that interact with estrogen signaling cascades, and (2) Evaluate the effects of FSS on the acquired resistance to endocrine therapy. A hallmark of the proposed technology is the ability to perform both bulk off-chip interrogation and cellular selection and on-chip single cell analysis using fluorescent microscopy to characterize the heterogeneous nature and response of individual cancer cells. These studies will provide new fundamental insight into the effects of FSS on estrogen signaling to identify novel mechanisms of endocrine resistance in ER+ breast cancer at metastatic sites, this has the potential to lead to novel therapies designed to treat metastatic ER+ breast cancer.

项目摘要 大约70％的乳腺癌患者将出现雌激素受体阳性（ER+）亚型。的 这些患者，大多数患者在治疗原发性肿瘤时最初会对内分泌疗法有反应。很遗憾， 转移性扩散后，其中许多患者会产生对内分泌疗法的抗性，从而导致 患者死亡率的显着增加，因为没有可行的转移性乳腺癌治疗方法。 转移后，当前的中位生存时间为5 - 10年，这加强了至关重要的需求 了解导致转移性肿瘤内分泌耐药性的细胞机制。内分泌 假设转移部位的抗性是通过多种机制发生的，包括：（i）丢失 雌激素受体，（ii）获取其他突变和/或（iii）雌激素和生长因子的改变 介导的信号级联。在转移期间，ER+乳腺癌细胞暴露于高幅度 流体剪切应力（FSS）（最多60 dyn/cm2）和流体诱导的变形在穿过脉管系统时。 先前的工作已经确定FSS诱导激酶途径的激活增加，包括相关的途径 在癌细胞系中的快速雌激素信号传导和相关的内分泌抗性中。不幸的是， FSS关于ER信号传导的调节和转移过程中ER+乳腺癌的生物适应 不完全理解。为了阐明FSS在转移性乳腺癌中如何驱动内分泌反应，我们提出 以下假设：ER+乳腺癌细胞暴露于FSS抑制ER表达并诱导 生长因子信号级联反应和随后的内分泌耐药性的激活。我们建议对此进行测试 假设利用模块化微流体平台，能够将乳腺癌细胞暴露于良好的控制中 FSS的均匀幅度和持续时间，这些FSS模拟了转移性传播过程中发生的原位条件。 具体而言，我们将（1）确定FSS如何改变雌激素受体的表达和生长因子途径，这些途径 与雌激素信号传导级联相互作用，（2）评估FSS对获得的抗性的影响 内分泌疗法。拟议技术的标志是能够进行两次大量外片询问 以及使用荧光显微镜的细胞选择和片上单细胞分析以表征 单个癌细胞的异质性和反应。这些研究将提供新的基本 深入了解FSS对雌激素信号传导的影响，以鉴定ER+中内分泌耐药性的新机制 转移性部位的乳腺癌有可能导致旨在治疗转移性的新型疗法 ER+乳腺癌。