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: 10451678
• 负责人: WILLIAM T MONROE
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451678
• 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%的乳腺癌患者会出现雌激素受体阳性（ER+）亚型。的 这些患者在治疗原发性肿瘤时，大多数最初会对内分泌治疗产生反应。不幸的是， 在转移扩散后，这些患者中的许多人对内分泌疗法产生抗性， 患者死亡率显著增加，因为对于转移性乳腺癌没有可行的治疗。 转移后，目前的中位生存时间为5-10年，这加强了对更好地治疗癌症的迫切需要。 了解导致转移性肿瘤内分泌治疗抵抗的细胞机制。内分泌 假设转移部位的耐药通过多种机制发生，包括：（i）在转移部位的细胞的丧失， 雌激素受体，（ii）获得额外的突变，和/或（iii）雌激素和生长因子的改变 介导的信号级联。在转移过程中，ER+乳腺癌细胞暴露于高强度的 流体剪切应力（FSS）（高达60 dyn/cm 2）和流体诱导变形，同时通过脉管系统。 先前的工作已经确定，FSS诱导激酶途径的激活增加，包括那些涉及 在癌细胞系中快速雌激素信号传导和相关的内分泌抗性中的作用。不幸的是， FSS对ER信号的调节和ER+乳腺癌在转移过程中的生物学适应性的影响 没有完全理解。为了阐明FSS如何驱动转移性乳腺癌的内分泌反应，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 生长因子信号级联的激活和随后的内分泌抗性。我们打算测试一下 假设利用能够将乳腺癌细胞暴露于良好控制的， 模拟转移扩散过程中发生的原位条件的均匀幅度和持续时间的FSS。 具体而言，我们将（1）确定FSS如何改变雌激素受体表达和生长因子途径， 与雌激素信号级联相互作用，和（2）评估FSS对获得性耐药性的影响。 内分泌治疗所提出的技术的一个特点是能够执行批量芯片外询问和 以及使用荧光显微镜进行细胞选择和芯片上单细胞分析，以表征 个体癌细胞的异质性和应答。这些研究将提供新的基础 深入了解FSS对雌激素信号传导的影响，以确定ER+中内分泌抵抗的新机制 乳腺癌转移部位，这有可能导致新的治疗方法，旨在治疗转移性 ER+乳腺癌。