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Departments of Experimental Therapeutics [K. L., W. J., C. K., M. S., Z. F.], Molecular Therapeutics [G. B. M., Z. F.], Radiation Oncology [K. K. A.], and Experimental Radiation Oncology [L. M.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

³ To whom requests for reprints should be addressed, at Unit 36, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: zfan{at}mdanderson.org

The phosphatidylinositol 3-kinase (PI-3K)/Akt pathway, regulated by its upstream growth factor receptor tyrosine kinases, plays a critical role in promoting cell proliferation and inhibiting cell death. The aim of this study was to determine whether the PI-3K/Akt activity contributes to the resistance of human breast cancer cells to ionizing radiation and whether inhibition of the PI-3K/Akt pathway could sensitize human breast cancer cells to radiotherapy. To determine a causal relationship between the activity of Akt and radioresistance in human breast cancer cells, MCF7 cells, transfected with constitutively active H-Ras (RadG12V) or constitutively active Akt, were chosen for analysis of the cell clonogenic survival fraction and induction of apoptosis after ionizing radiation. The PI-3K-specific inhibitor LY294002 was used to examine whether inhibition of PI-3K could sensitize these cells to radiation treatment. Our results indicate that the expression of constitutively active Ras (which activated Akt in a PI-3K-dependent manner) and the expression of constitutively active Akt (which caused a PI-3K-independent activation of Akt) each increased cellular resistance to radiation. Inhibition of PI-3K with LY294002 reverted the constitutively active Ras-mediated radioresistance but not the constitutively active Akt-mediated radioresistance. Our data suggest that Akt may be a potential target for enhancing the response to radiotherapy in patients with breast cancer.

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