Yong Weon Yi and Hyo Jin Kang contributed equally to this manuscript.
Article first published online: 4 APR 2012
Copyright © 2012 Wiley Periodicals, Inc.
Volume 52, Issue 9, pages 667–675, September 2013
How to Cite
Yi, Y. W., Kang, H. J., Kim, H. J., Hwang, J. S., Wang, A. and Bae, I. (2013), 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. Mol. Carcinog., 52: 667–675. doi: 10.1002/mc.21905
Conflicts of interest: The authors declare no conflict of interest.
- Issue published online: 10 AUG 2013
- Article first published online: 4 APR 2012
- Manuscript Accepted: 7 MAR 2012
- Manuscript Revised: 21 FEB 2012
- Manuscript Received: 14 DEC 2011
- constitutive activation;
- PI3K/AKT pathway;
- BRCA1-defective breast cancer;
- kinase inhibitor;
- chemotherapeutic agents;
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.