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Comprehensive analysis of oncogenic effects of PIK3CA mutations in human mammary epithelial cells

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Abstract

More than 20 different PIK3CA gene mutations were identified in breast cancer with different frequencies. Whether these breast cancer associated mutations have similar biological effects is largely unknown. In this study, we established a novel cell model using the lentivirus system to express 10 different PIK3CA genes (wild type and mutant) based on the human mammary epithelial cell MCF10A. We found that nine different PIK3CA mutants harbor different abilities to promote cell proliferation and EGF independent growth. In addition, most PIK3CA mutants (except for the wild type PIK3CA, the Q60K and the K111N mutants) had the ability to change the morphogenesis of the MCF10A cell in 3D Matrigel assay. Moreover, different PIK3CA mutants have different abilities to promote colony formation and cell invasion. We further observed that most of the PIK3CA mutants could activate p-AKT and p-p70-S6K in the absence of EGF stimulation. Finally, LY294002, a PI3K inhibitor, can effectively inhibit cell growth in cell lines with different PIK3CAs. Taken together, our results support the notion that different PIK3CA mutations differentially contribute to breast cancer transformation, and exploration of the therapeutic application of these mutations will benefit breast cancer patients with the PIK3CA mutations.

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Abbreviations

PI3K:

Phosphatidylinositol 3-kinase

CEF:

Chicken embryo fibroblasts

HMEC:

Human mammary epithelial cell

EGF:

Epidermal growth factor

ErbB2v-erb-b2:

Erythroblastic leukemia viral oncogene homolog

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Acknowledgements

This work was supported by start-up fund (to GW) from the Barbara Ann Karmanos Cancer Institute, Department of Pathology, Wayne State University. We also thank Mrs Courtney McCrimmon for editing the manuscript.

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Authors and Affiliations

  1. Breast Cancer Program, Karmanos Cancer Institute, Detroit, MI, USA

    Haijun Zhang, Gang Liu, Michele Dziubinski, Zengquan Yang, Stephen P. Ethier & Guojun Wu

  2. Genetics Research Center, Southeast University School of Medicine, Nanjing, 210009, Jiangsu Province, P. R. China

    Haijun Zhang

  3. Karmanos Cancer Institute, Department of Pathology, Wayne State University, HWCRC, Room 840.2, 4100 John R Street, Detroit, MI, 48201, USA

    Guojun Wu

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  1. Haijun Zhang
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  2. Gang Liu
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Correspondence to Guojun Wu.

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Zhang, H., Liu, G., Dziubinski, M. et al. Comprehensive analysis of oncogenic effects of PIK3CA mutations in human mammary epithelial cells. Breast Cancer Res Treat 112, 217–227 (2008). https://doi.org/10.1007/s10549-007-9847-6

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  • DOI: https://doi.org/10.1007/s10549-007-9847-6

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