Gene Expression Signatures of PI3K Signaling Are Associated with Low ER Levels and the Luminal B Subtype in Breast Cancer Cell Lines and Human Tumors, and in Patients Predicts Poor Outcome.

Background: Accumulating evidence suggests that both levels and activity of ER and progesterone receptor (PR) are dramatically influenced by growth factor receptor (GFR) signaling pathways, and that this crosstalk is a major determinant of both breast cancer (BC) progression and response to therapy. The phosphatidylinositol 3-kinase (PI3K) pathway, a key mediator of GFR signaling, is one of the most altered pathways in BC. We thus examined whether deregulated PI3K signaling in luminal ER+ breast tumors is associated with ER level and activity, molecular subtype, and outcome.Materials and Methods: To directly test for an association between ER levels and PI3K activation in BC, we defined a PI3K transcriptional signature as the set of genes either induced or repressed by PI3K inhibitors in the public Connectivity Map (CMap) expression profile dataset (www.broad.mit.edu/cmap). Using this signature, we assigned a PI3K activation score to each ER+ human breast tumor from two independent expression profile datasets (van de Vijver et al., n=226; Loi et al., n=348). Furthermore, within a broad panel of luminal BC cell lines, we compared the gene signature-based CMap PI3K score with a proteomic (Reversed Phase Proteomic Array, RPPA)-based PI3K score (which relied on protein measurement for PI3K signaling intermediates). We also compared the CMap-derived PI3K activation scores with scores based on a signature of PTEN loss in human breast tumors (Saal et al.), and on a signature of Akt activation in a transgenic mouse model (Majumder et al.).Results: Within ER+ tumors, ER mRNA level was negatively associated with the CMap PI3K activation score (van de Vijver: Pearson9s rs=-0.32, p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 31.