Characterizing an EMT signature in breast cancer

Stanford University, Stanford CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Breast cancer effects women of all races and ethnicities and is the second leading cause of cancer death in women in the United States. Breast cancer mortality results from the tumor acquiring the ability to invade and metastasize to different sites in the body. In order to invade and metastasize, cancer cells must first dissociate from one another and become motile. This process mirrors the epithelial-mesenchymal transition (EMT), a highly conserved process in embryonic development that occurs during tissue patterning. During EMT, epithelial cells lose polarity and the ability to make cell-cell contacts by altering the expression of several genes, ultimately leading to a more migratory, fibroblast-like "mesenchmymal" cell phenotype. There is strong evidence EMT occurs, at least transiently, during breast cancer progression. We propose to exploit the phenotypic differences between "epithelial-like" and "fibroblast-like" breast cancer cell lines in culture to explore the mechanisms of EMT. Based on our preliminary microarray data, we hypothesize that breast cancer cells in culture display varying extents of EMT. The goal of this proposal is to compare the global patterns of gene expression among epithelial-like and fibroblast-like breast cancer cell lines to identify and then to characterize a signature of EMT in breast cancer progression. In aim 1, breast cancer cell lines representing both "epithelial" and "fibroblast" morphologies will be profiled for gene expression using "whole- genome" DNA microarrays. Discriminatory gene-expression signatures reflecting EMT will be identified from microarray data, using supervised analysis methods. Candidate EMT "driver" genes will be identified by intersecting the EMT signature with genes found to be locally amplified by array-based comparative genomic hybridization (array CGH). In Aim 2, the prognostic value of the EMT gene signature will be evaluated by analyzing its coordinated expression and correlation with clinical outcomes in primary breast tumors, using publicly-available clinically-annotated breast cancer microarray expression datasets. In Aim 3, selected EMT signature genes will be evaluated by transfecting individual genes into "epithelial-like" breast epithelial cells in culture and then monitoring for morphologic and molecular evidence of EMT. Candidate EMT "driver" genes, i.e., those found also amplified in breast cancer, will be prioritized for analysis. Public Health: This study will improve our knowledge of EMT and provide tools for future exploration into the role of EMT in breast cancer. The knowledge and genes identified may prove important for the development of novel treatment strategies targeting EMT to prevent breast cancer progression. [unreadable] [unreadable] [unreadable]