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Identification of Gene Expression Profiles That Predict the Aggressive Behavior of Breast Cancer Cells

Departments of Cancer Research [D. A. Z., Y. G., L. W., H-L. L., P. H. J.] and Genomics and Gene Therapy [M. F. B., C. B., S. H.], Berlex Biosciences, Richmond, California 94804; Clontech Laboratories, Palo Alto, California 94303 [A. M.]; and Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan 48109 [S. P. E.]

With the goal of identifying genes that have an expression pattern that can facilitate the diagnosis of primary breast cancers (BCs) as well as the discovery of novel drug leads for BC treatment, we used cDNA hybridization arrays to analyze the gene expression profiles (GEPs) of nine weakly invasive and four highly invasive BC cell lines. Differences in gene expression between weakly and highly invasive BC cells were identified that enabled the definition of consensus GEPs for each invasive phenotype. To determine whether the consensus GEPs, comprising 24 genes, could be used to predict the aggressiveness of previously uncharacterized cells, gene expression levels and comparative invasive and migratory characteristics of nine additional human mammary epithelial cell strains/lines were determined. The results demonstrated that the GEP of a cell line is predictive of its invasive and migratory behavior, as manifest by the morphology of its colonies when cultured on a matrix of basement membrane constituents (i.e., Matrigel). We found that the expression of keratin 19 was consistently elevated in the less aggressive BC cell lines and that vimentin and fos-related antigen-1 (FRA-1) were consistently overexpressed in the more highly aggressive BC cells. Moreover, even without these three genes, the GEP of a cell line still accurately predicted the aggressiveness of the BC cell, indicating that the expression pattern of multiple genes may be used as BC prognosticators because single markers often fail to be predictive in clinical specimens.

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