Abstract

Previously, we investigated the induction effect of LRP16 expression by estrogen (E2) and established a feed-forward mechanism that activated ERa transactivation in estrogen-dependent epithelial cancer cells. LRP16 is required for ERa signaling transduction by functioning as an ERa coactivator. In this study, we demonstrated that LRP16 expression was up-regulated in E2-responsive BG-1 ovarian cancer cells, but was down-regulated in estrogen-resistant SKOV3 ovarian cancer cells. Pure estrogen antagonist ICI 182 780 did not affect LRP16 expression in SKOV3 cell. The unliganded ERa up-regulated LRP16 expression and enhanced LRP16 promoter activity in SKOV3 cells; however, this induction was blocked by estrogen stimulation. Results from chromatin immunoprecipitation experiment revealed a strong recruitment of the unliganded ERa at LRP16 promoter in the absence of estrogen; however, ERa was largely released from the DNA upon E2 stimulation. Although LRP16 did not significantly change the proliferation rate of SKOV3 cells, it seemed to slightly modulate the growth responsiveness of cells to E2. Knockdown of LRP16 by RNA interference in SKOV3 cells markedly attenuated estrogen response element-dependent ERa reporter gene activity and E2-induced c-myc expression. Our study suggests a novel mechanism of estrogen resistance of ovarian cancer by which estrogen-repressed signaling pathway antagonizes estrogen-activated signaling transduction.

Key words: LRP16, estrogen, estrogen receptor a, SKOV3