Functional characterization of MKP3 in the regulation of estrogen receptor-alpha in ovarian cancer

Abstract

Despite recent advances in ovarian cancer treatment, the associated mortality has not improved significantly. Insight into the molecular mechanisms involved inthe etiology and progression of the disease would help in the search for new strategies that would translate into better survival.Two-thirds of all ovarian cancers over-express estrogen receptor-alpha (ER-alpha). High ER-alpha expression levels have been implicated in the tumorigenesis, prognosis and response to treatment but the exact mechanism of ER regulation is still unclear. Previous report indicated that ERK1/2 activates Forkhead box M1 (FOXM1) transcriptional factor which in turn increases ER-alpha expression in breast cancer. In our own work, we found that Dual specificity MAPK phophatase 3 (MKP3), a negative regulator of ERK1/2, was downregulated in ovarian cancer. In addition, we have also found that enforced expression of MKP3 inhibited the ERK1/2 activity and reduced the expressions of FOXM1 and ER-alpha. Conversely, depletion of endogenous of MKP3 by RNAi elevated the ERK1/2 activity, and FOXM1 and ER-alpha expression in ovarian cancer cells. Based on these findings, we hypothesize that the frequent under-expression of MKP3 leads to aberrant activation of ERK1/2 activity and increased ER-alpha expression through ERK1/2/FOXM1/ER-alpha signaling pathway in ovarian cancer. To further characterize the MKP3/ERK1/2/FOXM1/ER-alpha signaling pathway in ovarian cancer cells, we are examining the molecular mechanism in silencing of MKP3 in ovarian cancer, and testing whether the restoration of MKP3 in MKP3-deficient ovarian cancer cells may sensitize these cells to anti-estrogenic treatment. Our data may shed insight into the role of MKP3 in the regulation of ER-alpha through ERK1/2 signaling pathway and ERK activation-dependent FOXM1 transcriptional activity. This would allow a better understanding of the role of hormonal therapy and it might also provide a scientific basis for future development of novel treatments.