[NVP-BKM120 in combination with letrozole inhibit human breast cancer stem cells via PI3K/mTOR pathway]

Objective: Breast cancer stem cells (BCSC) have been suggested to have clinical implications for cancer therapeutics because of their proposed role in chemo-resistance. The aim of this study was to investigate effects of BCSC on endocrine therapy response by regulating PI3K/Akt/mTOR signaling pathway. Methods: We evaluated the susceptibility of BCSC to NVP-BKM120 (BKM120), a new generation of PI3K-specific inhibitor, when used individually or in combination with letrozole in vivo. For this, a stem-like cell population (SC) was enriched from breast cancer cell line MCF-7 after mammosphere cultures. We have constructed high aromatase expression BCSC (BCSC-CYP19) and non-stem cells (MCF-7-CYP19) subcloning. We demonstrate BKM120 inhibits growth, generation of drug-resistant derivatives and SC formation in BCSC-CYP19 and MCF-7-CYP19. Result: BKM120 could inhibit BCSC-CYP19 growth by dose-dependence, reduce migration and colony formation of BCSC-CYP19, and also significantly reduced expression of PI3K, Akt1 and S6. Combined BKM120 and letrozolecaninhibit BCSC-CYP19 growth and proliferation, make BCSC-CYP19 stayed in G0-G1 phase increasing significantly to induce early apoptosis, and down-regulate expression of PI3K, Akt1 and S6. Conclusion: PI3K/Akt/mTOR pathway effects on letrozole resistance by regulating BCBSs characteristics. Combination of PI3K inhibitor BKM120 and letrozole could reduce letrozole resistance.