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Mechanisms of metformin-induced c-MET downregulation in triple-negative breast cancer

二甲双胍诱导三阴性乳腺癌 c-MET 下调的机制

基本信息

批准号：
10238925
负责人：
Dana Marie Austin Gant
金额：
$ 3.61万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-12 至 2022-09-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238925
关键词：
Address African American Animals Antineoplastic Agents Apoptosis Basal Cell Binding Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Cancer Burden Cancer Cell Growth Cell Proliferation Cell model Cells Clinical Communication Community Outreach Critical Pathways Data Development Diabetes Mellitus Diagnosis Down-Regulation ERBB2 gene Embryonic Development Epidermal Growth Factor Receptor FRAP1 gene Future Genetic Transcription Grant Hormone Receptor Human IGF1R gene In Vitro Inhibition of Cell Proliferation Knowledge Lentivirus Literature MDA MB 231 MDA-MB-468 MET gene Malignant Neoplasms Mammary Neoplasms Mediating Metformin Molecular Molecular Target Mouse Mammary Tumor Virus Mus Mutate Myoepithelial Neoplasm Metastasis Non-Insulin-Dependent Diabetes Mellitus Oncogenic Organogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Plant Roots Population Premenopause Prevention Process Prognosis Proteins RNA Receptor Protein-Tyrosine Kinases Recurrence Regulation Reporting Research Project Grants Risk Role STAT3 gene Scientist Signal Transduction Stat3 Signaling Pathway Testing Therapeutic Therapeutic Agents Time Tissues Training Translating United States WNT Signaling Pathway Woman Work Writing aggressive breast cancer anti-cancer base beta catenin breast cancer diagnosis cancer cell cancer health disparity cancer recurrence cancer stem cell cancer subtypes cell growth cell growth regulation chromatin immunoprecipitation effective therapy epithelial to mesenchymal transition experimental study health disparity human model in vivo insight knock-down malignant breast neoplasm mammary molecular marker mortality novel novel therapeutics overexpression premalignant promoter receptor refractory cancer safe patient self-renewal small hairpin RNA stem cell self renewal stem cells stemness therapeutic target transcription factor treatment strategy triple-negative invasive breast carcinoma tumor tumor initiation

项目摘要

PROJECT SUMMARY Over 250,000 new cases of invasive breast cancer are expected to be diagnosed in the United States each year. Triple-negative breast cancer is a breast cancer subtype that accounts for 20% of all breast cancers diagnosed. Approximately 50,000 new cases of triple-negative breast cancer are diagnosed each year. Triple- negative breast cancer is also noted as a health disparity, being that it is most common in African-American women. Unfortunately, triple-negative breast cancer is associated with poor prognosis, often spreading to other tissues resulting in a mortality rate. This type of breast cancer is very difficult to treat because it lacks common markers targeted by cancer drugs. Therefore, scientists are developing new drugs to target molecular markers found in triple-negative breast cancers. With this, led to the testing of metformin, a drug already widely used to treat diabetes, for the treatment of triple-negative breast cancer. Interestingly, scientists discovered that fewer diabetes patients taking metformin developed cancer over time. Although metformin is safe for patients to take, the mechanism by which metformin kills cancer cells is not fully understood. The objective of this study is to investigate the mechanism of metformin-mediated c-MET regulation in its killing of basal like breast cancer (BLBC)/TNBC cells. Based on previous studies and our preliminary data, we hypothesize that downregulation of c-MET and the associated inhibition of cell proliferation and CSC self-renewal is a critical determinant of metformin-mediated inhibition of basal-like/TNBC cells. The specific aims are: 1) To determine the effects of metformin-induced c-MET inhibition on TNBC cell growth and stemness; 2) To determine the molecular mechanism of metformin-induced c-MET downregulation; and 3) To determine the impact of metformin- induced c-MET downregulation on Wnt signaling in cancer stem cell stemness inhibition. At the end of this project, we hope to have an understanding of how metformin kills triple-negative breast cancer cells and how this can be translated to future animal and human studies. In addition to research project accomplishment, I will also gain specific training in professional communication, grant writing, community outreach, and studies on cancer health disparity issues. Ultimately, the knowledge gained from our work will contribute to the elimination of cancer-related challenges associated with triple-negative breast and may be applied to other cancers to reduce the overall cancer burden.

项目总结预计美国将分别诊断出超过25万例浸润性乳腺癌新病例年。三阴性乳腺癌是一种乳腺癌亚型，占所有乳腺癌的20%。诊断出来了。每年大约有50,000例三阴性乳腺癌新病例被诊断出来。三重- 阴性乳腺癌也被认为是一种健康差距，因为它在非裔美国人中最常见。女人。不幸的是，三阴性乳腺癌与预后不良有关，通常会扩散到其他导致死亡率的组织。这种类型的乳腺癌很难治疗，因为它缺乏常见的抗癌药物靶向的标志物。因此，科学家们正在开发针对分子标记的新药。在三阴性乳腺癌中发现。由此，导致了二甲双胍的测试，这种药物已经被广泛用于治疗糖尿病，用于治疗三阴性乳腺癌。有趣的是，科学家发现更少的人随着时间的推移，服用二甲双胍的糖尿病患者会患上癌症。虽然患者服用二甲双胍是安全的，二甲双胍杀死癌细胞的机制尚不完全清楚。这项研究的目的是二甲双胍介导的c-met基因对基底细胞样乳腺癌杀伤作用机制的研究 (BLBC)/TNBC细胞。根据之前的研究和我们的初步数据，我们假设下调监管 C-Met的表达及其对细胞增殖和CSC自我更新的抑制是二甲双胍对基底样细胞/TNBC细胞的抑制具体目标是：1)确定二甲双胍诱导的c-met对TNBC细胞生长和干性的抑制作用；2)确定分子二甲双胍诱导c-met下调的机制；3)确定二甲双胍对c-MET的影响。肿瘤干细胞干细胞抑制中c-met对Wnt信号的下调作用。在这个结束的时候项目，我们希望了解二甲双胍是如何杀死三阴性乳腺癌细胞的，以及如何这可以转化为未来的动物和人类研究。除了研究项目成就外，我还还将在专业交流、拨款撰写、社区推广和学习方面获得具体培训关于癌症健康差距的问题。最终，我们从工作中获得的知识将有助于消除与三阴性乳房相关的癌症相关挑战，并可能适用于其他减少癌症患者的总体癌症负担。