Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells

Authors

  • Yong Weon Yi,

    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
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  • Hyo Jin Kang,

    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
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  • Hee Jeong Kim,

    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
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  • Jae Seok Hwang,

    1. Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
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  • Antai Wang,

    1. Department of Biostatistics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
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  • Insoo Bae

    Corresponding author
    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
    2. Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
    3. Department of Nanobiomedical Science and WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea
    • Department of Oncology and Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.
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  • Yong Weon Yi and Hyo Jin Kang contributed equally to this manuscript.

  • Conflicts of interest: The authors declare no conflict of interest.

Abstract

Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1-defective human breast cancer cells. Levels of phospho-AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho-AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de-sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI-103, and BEZ235, showed anti-proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti-proliferative effects of gemcitabine by enhancing caspase-3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1-defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers. © 2012 Wiley Periodicals, Inc.

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