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

Sherene Loi, Benjamin Haibe-Kains, Samira Majjaj, Francoise Lallemand, Virginie Durbecq, Denis Larsimont, Ana M. Gonzalez-Angulo, Lajos Pusztai, W. Fraser Symmans, Alberto Bardelli, Paul Ellis, Andrew N.J. Tutt, Cheryl E. Gillett, Bryan T. Hennessy, Gordon Mills, Wayne A. Phillips, Martine J. Piccart, Terence P. Speed, Grant A. McArthur, Christos Sotiriou

Research output: Contribution to journalArticle

249 Citations (Scopus)

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+/HER2-BC 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.

Original languageEnglish (US)
Pages (from-to)10208-10213
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number22
DOIs
StatePublished - Jun 1 2010
Externally publishedYes

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Estrogen Receptors
Breast Neoplasms
Mutation
Genes
Tamoxifen
Phosphatidylinositol 3-Kinases
Gene Expression
mechanistic target of rapamycin complex 1
Exons
Theoretical Models
Phosphotransferases
Phenotype
Cell Line

Keywords

  • Gene expression profiling
  • PI3 kinase

ASJC Scopus subject areas

  • General

Cite this

PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. / Loi, Sherene; Haibe-Kains, Benjamin; Majjaj, Samira; Lallemand, Francoise; Durbecq, Virginie; Larsimont, Denis; Gonzalez-Angulo, Ana M.; Pusztai, Lajos; Symmans, W. Fraser; Bardelli, Alberto; Ellis, Paul; Tutt, Andrew N.J.; Gillett, Cheryl E.; Hennessy, Bryan T.; Mills, Gordon; Phillips, Wayne A.; Piccart, Martine J.; Speed, Terence P.; McArthur, Grant A.; Sotiriou, Christos.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 22, 01.06.2010, p. 10208-10213.

Research output: Contribution to journalArticle

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, G, Phillips, WA, Piccart, MJ, Speed, TP, McArthur, GA & Sotiriou, C 2010, 'PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 22, pp. 10208-10213. https://doi.org/10.1073/pnas.0907011107
Loi, Sherene ; Haibe-Kains, Benjamin ; Majjaj, Samira ; Lallemand, Francoise ; Durbecq, Virginie ; Larsimont, Denis ; Gonzalez-Angulo, Ana M. ; Pusztai, Lajos ; Symmans, W. Fraser ; Bardelli, Alberto ; Ellis, Paul ; Tutt, Andrew N.J. ; Gillett, Cheryl E. ; Hennessy, Bryan T. ; Mills, Gordon ; Phillips, Wayne A. ; Piccart, Martine J. ; Speed, Terence P. ; McArthur, Grant A. ; Sotiriou, Christos. / PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 22. pp. 10208-10213.
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AU - Lallemand, Francoise

AU - Durbecq, Virginie

AU - Larsimont, Denis

AU - Gonzalez-Angulo, Ana M.

AU - Pusztai, Lajos

AU - Symmans, W. Fraser

AU - Bardelli, Alberto

AU - Ellis, Paul

AU - Tutt, Andrew N.J.

AU - Gillett, Cheryl E.

AU - Hennessy, Bryan T.

AU - Mills, Gordon

AU - Phillips, Wayne A.

AU - Piccart, Martine J.

AU - Speed, Terence P.

AU - McArthur, Grant A.

AU - Sotiriou, Christos

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