Angiotensin II/Angiotensin II Type I Receptor (AT1R) Signaling Promotes MCF-7 Breast Cancer Cells Survival via PI3-Kinase/Akt Pathway

Angiotensin II (Ang II) is a bioactive peptide of the renin-angiotensin system, acting not only as a vasoconstrictor but also as a growth promoter via angiotensin II type I receptor (AT1R) in some cancer. In this study, we examined the mechanisms by which Ang II affected the cell proliferation in AT1R-positive MCF-7 human breast cancer cells. Ang II stimulated the growth of breast cancer cells in a dose- and time-dependent manner. The maximal proliferation effect on MCF-7 cells was obtained with 10(-4) M Ang II at 24 h. Losartan (10(-5) M, an AT1R antagonist) significantly decreased the level of Ang-II-induced proliferative effects, whereas PD123319 (10(-5) M, an AT2R antagonist) had no effects. Moreover, Ang II could significantly accelerate S-phase progression, which was inhibited by losartan (10(-5) M) or LY294002 (50 mu M, a PI3-kinase inhibitor). In addition, Ang II caused rapid activation of p-Akt in a dose- and time-dependent manner. 10(-4) M Ang II induced a significant increase of p-Akt in 15 min. The peak level of p-Akt could be persisted for at least 6 h. Among the signaling molecules downstream of Akt, we revealed that Ang II also significantly upregulated CyclinDI, GSK3 beta, and downregulated p27. Pretreatment with losartan (10(-5) M) or LY294002 (50 mu M) could significantly suppress these effects of Ang II. These findings suggest that Ang II plays a role in the growth of AT1R-positive breast cancer cells through PI3-kinase/Akt pathway activation. Therefore, targeting Ang II/AT1R signaling could be a novel therapeutic for breast cancer. J. Cell. Physiol. 225: 168-173, 2010. (C) 2010 Wiley-Liss, Inc.