An integrative genomic and proteomic analysis of pik3ca, pten, and akt mutations in breast cancer.
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Abstract
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 PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor–positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor–positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor–positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 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 PIK3CA 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 PIK3CA 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]
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Basal-like cancers rarely have PIK3CA mutations.
“Despite high pathway activity, basal-like cancers rarely display PIK3CA (PI3K catalytic domain) mutations (48).”
From Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer (2014) · cites this paper as [48]
[Parameter] reflects the activity of phosphatases like PTEN which is lost in many cancers.
“Finally, reflects the activity of phosphatases like phosphatase and tensin homolog (PTEN) which is lost in many cancers [26].”
From Optimal Experimental Design for Parameter Estimation of a Cell Signaling Model (2009) · cites this paper as [26]
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- Authors
- Stemke-Hale, K., Gonzalez-Angulo, A. M., Lluch, A., Neve, R. M., Kuo, W.-L., Davies, M., Carey, M., Hu, Z., Guan, Y., Sahin, A., Symmans, W. F., Pusztai, L., Nolden, L. K., Horlings, H., Berns, K., Hung, M.-C., van de Vijver, M. J., Valero, V., Gray, J. W., Bernards, R., Mills, G. B., & Hennessy, B. T.
- Affiliations
- 1Systems Biology, Departments of
- The University of Texas MD Anderson Cancer Center (US)
- Hospital Clínico Universitario de Valencia (ES)
- Lawrence Berkeley National Laboratory (US)
- 4Pathology,
- 2Breast Medical Oncology,
- 10Division of Experimental Therapy and
- The Netherlands Cancer Institute (NL)
- 5Molecular and Cellular Oncology, and
- 11Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands
- ORCID
- Venue
- Cancer Research
- Published
- 2008-08-01
- Volume
- 68
- Issue
- 15
- Pages
- 6084-6091
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2680495
- OpenAlex
- W2106036365
- Cited by
- 1,054
- References
- 29
- Citations by year
- 2026: 20 · 2025: 27 · 2024: 46 · 2023: 57 · 2022: 50 · 2021: 65 · 2020: 64 · 2019: 46 · 2018: 54 · 2017: 61 · 2016: 62 · 2015: 63 · 2014: 89 · 2013: 71 · 2012: 81
- FWCI
- 26.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- University of North Texas Digital Library (University of North Texas) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- National Institutes of Health (5k23ca121994-03)
- National Cancer Institute (R21CA120248, P50CA098258, 1K23CA121994-01), K23-CA121994, R01CA109311, P50CA058207, P01CA099031, P50CA083639, P30CA016672, U54CA112970)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- breast cancer, PIK3CA mutation, PTEN loss, AKT1 mutation, PI3K/Akt signaling, hormone receptor-positive breast cancer, HER2-positive breast cancer, basal-like breast cancer, tamoxifen response, LY294002, breast cancer cell lines, tumor subtypes
- MeSH terms
- Breast Neoplasms, Cell Division, Female, Humans, Mutation, Phosphatidylinositol 3-Kinases, Genomics, Proteomics, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Class I Phosphatidylinositol 3-Kinases
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