Estrogen stimulates the invasion of ovarian cancer cells via activation of the PI3K/AKT pathway and regulation of its downstream targets E-cadherin and α-actinin-4

Previous studies by our group revealed that the phosphoinositide 3-kinase (PI3K)/AKT pathway was involved in estrogen-induced metastasis in ovarian cancer cells. In the present study, the role and mechanism of estrogen-induced invasion was further explored using a stable short hairpin RNA (shRNA) estrogen receptor alpha/beta (ER alpha/beta) SKOV3 cell line when ER alpha and ER beta were knocked down by lentiviral infection. The effects of estrogen and LY294002, a PI3K inhibitor, on the invasion of shRNA ER alpha/beta SKOV3 cells were evaluated in vitro and in vivo. 17-beta estradiol promoted cell invasion, activated phosphorylated AKT in a dose- and time-dependent manner, decreased E-cadherin and increased cytoplasmic alpha-actinin-4 expression. When the PI3K/AKT pathway was suppressed by LY294002, the effect of estrogen was attenuated. Estrogen stimulated the growth of shRNA ER alpha/beta SKOV3 xenograft tumors in nude mice, whereas LY294002 inhibited the growth and antagonized the effect of estrogen. The results indicate that estrogen promotes the invasion of ovarian cancer cells via activation of the PI3K/AKT pathway, downregulation of E-cadherin and upregulation of alpha-actinin-4 in an ER-independent manner. Inhibiting the PI3K/AKT pathway may be a useful treatment for ovarian carcinoma.