Pathway activation signatures of breast cancer predict molecular subtype and drug sensitivity

A31

Breast cancer represents the highest incidence of cancer in women in the United States and Europe, with an estimated 182,460 new cases expected to occur in the US this year (1). Gene-expression profiling of breast cancer has confirmed the hypothesis that breast cancer is not a single disease, but can in fact be classified as subtypes that exhibit distinct histopathology, clinical outcomes, and therapeutic sensitivity. Basal-like tumors are a subtype that has been shown to be particularly associated with poor prognosis. The molecular pathways that underlie and drive the progression of basal-like tumors are poorly understood, and there are currently no approved targeted therapies for basal-like breast cancer. Therefore, basal-like breast cancer represents a serious unmet medical need.
 Recent efforts at understanding breast cancer subtypes have typically focused on gene expression analysis. In this poster, we demonstrate classification of cell lines representing breast cancer subtypes can be accomplished through pathway activation profiling using reverse phase protein microarrays to detect phosphorylation of pathway-specific proteins. Bioinformatic analysis revealed distinct pathway activation signatures between respective subtypes and that phosphoprotein endpoints largely recapitulate molecular classification determined by gene expression analyses. We were able to correlate observed pathway activation to sensitivity of targeted therapies to components of specific cellular pathways. Basal-like breast cancer cells in particular demonstrated high activation of the EGFR signaling pathway, including Erk1/2. Conversely, we show that luminal and HER2 amplified cell lines are enriched in phosphorylation of components of the PI3 kinase/Akt and mTor pathways. Finally, we show that activation of particular pathway modules is predictive of in vitro response to targeted inhibitors of MEK1/2 and PI3 kinase and that these modules are activated in a subtype-specific manner in breast cancer.