Investigating mechanisms of chemoresistance in triple-negative breast cancer

研究三阴性乳腺癌的化疗耐药机制

• 批准号: 10549343
• 负责人: Madeleine Julie Oudin
• 金额: $ 34.01万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-11 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549343
• 关键词: Adipocytes; Adjuvant Chemotherapy; Affect; Aftercare; Automobile Driving; Breast Cancer Cell; Breast Cancer Patient; Cancer Burden; Caspase; Cathepsins B; Cell secretion; Cessation of life; Chemoresistance; Clinical; Collagen; Collagen Type IV; Crosslinker; Data; Development; Drug resistance; Endothelial Cells; Environment; Excision; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Gene Expression Profile; Glycoproteins; Goals; Human; In Vitro; Individual; Invaded; Laminin; Macrophage; Malignant Neoplasms; Mammary Neoplasms; Metastasis Induction; Metastatic/Recurrent; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Paclitaxel; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Play; Population; Process; Property; Proteins; Proteoglycan; Recurrence; Relapse; Research; Residual Cancers; Resistance; Role; Sampling; Signal Transduction; Structural Protein; Structure; Testing; Therapeutic; Tissues; Tumor Tissue; Up-Regulation; cell motility; cell type; chemotherapy; improved; in vivo; insight; malignant breast neoplasm; neoplastic cell; novel; prevent; response; standard of care; therapy outcome; three-dimensional modeling; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary Chemotherapy remains the standard of care for patients with triple-negative breast cancer (TNBC), which affects 20% of patients with breast cancer. However, 50% of patients with localized TNBC treated with neoadjuvant chemotherapy display residual cancer burden after treatment and up to 25% of patients who receive this treatment will suffer metastatic recurrence within five years. The poor association between chemotherapy and patient outcome emphasizes two major problems for TNBC patients: chemoresistance, where tumor cells within the local environment are protected and do not die in response to chemotherapy, and chemotherapy-induced metastasis, where chemotherapy-induced changes in tumor intrinsic properties and the tumor microenvironment drive invasion which leads to recurrence. Previous studies have demonstrated that cell migration and extracellular matrix (ECM) remodeling are associated with chemoresistant TNBC. The goal of this proposal is to understand the mechanisms by which the ECM contributes to chemoresistance and chemotherapy-induced metastasis in TNBC. We provide preliminary data that individual proteins upregulated in TNBC tumors drive resistance to chemotherapy drug Paclitaxel and that expression of Cathepsin B (CTSB), a protease which degrades these ECM proteins into small fragments, protects against the development of chemoresistance. We will dissect the mechanism by which the protease CTSB and the ECM proteins it degrades influence response to Paclitaxel in TNBC and whether these fragments can be used to track and target chemoresistance in vivo. We have also found that chemotherapy treatment leads to changes in the ECM composition of mammary tumors. Specifically, Paclitaxel treatment leads to an increased abundance of Collagen IV, an ECM protein which promote invasion and metastasis in TNBC. Our goal is to determine the cell types that secrete ECM proteins such as Collagen IV after chemotherapy treatment, determine the contribution of these ECM proteins to chemotherapy-induced metastasis, and whether these pathways can be targeted to prevent the development of recurrence. Upon successful completion of the proposed research, our contribution is expected to be an understanding of how ECM proteins upregulated in TNBC tumors contribute to chemoresistance and how chemotherapy alters the ECM to promote recurrence and metastatic dissemination. These contributions will be significant because all TNBC patients receive chemotherapy and metastatic recurrence is a current unmet clinical need. Results from these studies will provide novel conceptual insights on mechanisms of chemoresistance and chemotherapy-induced metastasis and will allow us to develop new strategies to track, predict and overcome chemoresistance in TNBC.

项目总结