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

项目摘要 预计美国每年将诊断出超过25万例新的浸润性乳腺癌病例， 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。每年大约有50，000例新的三阴性乳腺癌病例被诊断出来。三- 阴性乳腺癌也被认为是一种健康差异，因为它在非洲裔美国人中最常见。 妇女不幸的是，三阴性乳腺癌与预后不良有关，通常会扩散到其他组织。 导致死亡率。这种类型的乳腺癌很难治疗，因为它缺乏共同的 癌症药物靶向的标记物。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。有了这个，导致了二甲双胍的测试，这种药物已经广泛用于 治疗糖尿病，治疗三阴性乳腺癌。有趣的是，科学家们发现， 服用二甲双胍的糖尿病患者随着时间的推移发生癌症。虽然二甲双胍对患者是安全的， 二甲双胍杀死癌细胞的机制还不完全清楚。本研究的目的是 探讨二甲双胍介导c-MET杀伤基底细胞样乳腺癌的机制 （BLBC）/TNBC细胞。基于以前的研究和我们的初步数据，我们假设下调 c-MET和相关的细胞增殖和CSC自我更新的抑制是C-MET的关键决定因素。 二甲双胍介导的基底样/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细胞生长和干细胞的抑制; 2）确定二甲双胍诱导的c-MET对TNBC细胞生长和干细胞的抑制的分子机制。 二甲双胍诱导的c-MET下调的机制;和3）为了确定二甲双胍对c-MET的影响， 在癌症干细胞干性抑制中诱导c-MET下调Wnt信号传导。于年底 项目，我们希望了解二甲双胍如何杀死三阴性乳腺癌细胞， 这可以转化为未来的动物和人类研究。除了完成研究项目外，我 还将获得专业沟通，赠款写作，社区外展和研究方面的具体培训 关于癌症健康差异的问题。最终，从我们的工作中获得的知识将有助于 消除与三阴性乳腺癌相关的癌症相关挑战，并可应用于其他 癌症，以减少整体癌症负担。

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.