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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结