PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer

Loi, S; Haibe-Kains, B; Majjaj, S; Lallemand, F; Durbecq, V; Larsimont, D; Gonzalez-Angulo, AM; Pusztai, L; Symmans, WF; Bardelli, A; Ellis, P; Tutt, ANJ; Gillett, CE; Hennessy, BT; Mills, GB; Phillips, WA; Piccart, MJ; Speed, TP; McArthur, GA; Sotiriou, C

Author(s): Loi, S; Haibe-Kains, B; Majjaj, S; Lallemand, F; Durbecq, V; Larsimont, D; Gonzalez-Angulo, AM; Pusztai, L; Symmans, WF; Bardelli, A; Ellis, P; Tutt, ANJ; Gillett, CE; Hennessy, BT; Mills, GB; Phillips, WA; Piccart, MJ; Speed, TP; McArthur, GA; Sotiriou, C;
Details: Publication Year 2010-06-01,Volume 107,Issue #22,Page 10208-10213
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
Abstract: PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor-positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions have been hypothesized to render tumors highly sensitive to therapeutic PI3K/mTOR inhibition. By analyzing gene expression and protein data from nearly 1,800 human BCs, we report that a PIK3CA mutation associated gene signature (PIK3CA-GS) derived from exon 20 (kinase domain) mutations was able to predict PIK3CA mutation status in two independent datasets, strongly suggesting a characteristic set of gene expression-induced changes. However, in ER+/HER2BC despite pathway activation, PIK3CA mutations were associated with a phenotype of relatively low mTORC1 signaling and a good prognosis with tamoxifen monotherapy. The relationship between clinical outcome and the PIK3CA-GS wasalso assessed. Although the PIK3CA-GS was not associated with prognosis in ER- and HER2+ BC, it could identify better clinical outcomes in ER+/HER2-disease. In ER+ BC cell lines, PIK3CA mutations were also associated with sensitivity to tamoxifen. These findings could have important implications for the treatment of PIK3CA-mutant BCs and the development of PI3K/mTOR inhibitors.
Publisher: NATL ACAD SCIENCES
Keywords: TYROSINE PHOSPHORYLATION; EXPRESSION PROFILES; 3-KINASE MUTATIONS; MOLECULAR SUBTYPES; INSULIN-RECEPTOR; POOR-PROGNOSIS; AKT; PATHWAY; TUMORS; PTEN
Publisher's Version: https://doi.org/10.1073/pnas.0907011107
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2010-06-01 12:00:00