Exploring the Biological Mechanism of Mammalian Phosphatidylinositol-3-Kinase/Protein Kinase B/Target of Rapamycin (PI3K/Akt/mTOR) Signaling in the Treatment of Triple-Negative Breast Cancer (TNBC)

Abstract

We aimed to study the biological effect of PI3K/Akt/mTOR signal pathway on the treatment of TNBC, along with the efficiency of PI3K inhibitor BKM120, mTOR inhibitor PF-4708671 and dual inhibitor GDC-0980 on treating breast cancer in terms of proliferation and apoptosis utilizing MDA-MB-213 cell line, as well as on the expression of S6K1. The expressions of PI3K, mTOR and Akt in TNBC and paired adjacent tissues were detected by PCR. After treatment with BKM120, PF-4708671 and GDC-0980 for 24, 48, 72 and 96 hours, CCK-8 method was employed to assess the proliferation and apoptosis curves of the MDA-MB-231 cell line, the expression of S6K1 was detected by Western Blot. Expressions of PI3K, mTOR and Akt in TNBC tissues were significantly increased than those in normal specimens (P = 0.000); Compared with control group, cell proliferation treated with three inhibitors was significantly impeded, of which the inhibitory effect of PF-5708671 was slightly stronger than BKM120, while the strongest inhibitory effect was observed for GDC-0980 treatment. After 48 hours treatment, the expression intensity of p-mTOR, p-PI3K and S6K1 in MDA-MB-213 cells treated with BKM120, PF-4708671 and GDC-0980 was decreased, of which the suppression of p-mTOR, p-PI3K and S6K1 by GDC-0980 was stronger than other groups. The inclined expression of PI3K, mTOR and Akt was observed in TNBC tissues. The antagonists targeting the PI3K/Akt/mTOR signaling could inhibit the proliferation of triple-negative breast cancer cell line, of which the dual inhibitor exerted the strongest inhibition effect, and could decreased the expression of S6K1 and activity. The antagonists targeting the PI3K/Akt/mTOR signal transduction showed a promising prospect in the treatment of TNBC.