Data from An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer

Abstract

<div>Abstract<p>Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy–based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of <i>PIK3CA, AKT</i>, and <i>PTEN</i> mutations and the effects of <i>PIK3CA</i> mutations on responsiveness to PI3K inhibition <i>in vitro</i> and on outcome after adjuvant tamoxifen. <i>PIK3CA</i> mutations were more common in hormone receptor–positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). <i>AKT1</i> (1.4%) and <i>PTEN</i> (2.3%) mutations were restricted to hormone receptor–positive cancers. Unlike <i>AKT1</i> mutations that were absent from cell lines, <i>PIK3CA</i> (39%) and <i>PTEN</i> (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not <i>AKT1</i> mutations during adaptation to culture. <i>PIK3CA</i> mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor–positive breast cancer patients. <i>PIK3CA</i> mutations, in comparison with PTEN loss and <i>AKT1</i> mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and <i>PIK3CA</i> mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did <i>PIK3CA</i> mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor–positive breast cancer. [Cancer Res 2008;68(15):6084–91]</p></div>