Detachment-Induced Autophagy and Breast Cancer Cell Survival.

摘要

Subject: During breast cancer progression and metastasis, tumor cells acquire the ability to survive and grow in stressful microenvironments. The genetic lesions that drive proliferation and prevent cell death during tumor development are well understood, however, less is known about the contributions of pathways that allow cells to cope with environmental stress, such as autophagy. Purpose: Although autophagy is known to aid in cell survival in response to a wide range of stress stimuli, it remains unclear whether autophagy enhances or suppresses the development and progression of breast cancer (Mizushima et al., 2008). Understanding the role of autophagy during stress in the context of breast cancer cells will allow us to determine if autophagy could be a valuable drug target for breast cancer treatment. Scope: The goals of this research project are to: 1) Determine if breast epithelial cells (MCF10A cells) expressing oncogenes mutated in breast cancer initiate autophagy during extracellular matrix detachment, 2) Determine if autophagy inhibition promotes cell death during extracellular matrix detachment, alters 3D morphogenesis, and contributes to oncogenic transformation, and 3) Determine if autophagy suppression increases cell death and alters transformation in established breast cancer cell lines. Over the entire funding period of this award we have found that autophagy is induced in oncogene expressing breast epithelial cells and in two breast cancer cells lines in response to extracellular matrix detachemnet. Importantly we have found that autophagy is critical for the fitness of these cells as autophagy inhibition decreases the transformation potential of oncogene expressing breast epithelial cells and a breast cancer cell line, MDA-MB-231. Finally.