Several lines of evidence indicate that Wip1 may be regulated in a steroid-dependent manner. First, Wip1 is over-expressed in a number of cancers regulated by steroids such as breast cancer and ovarian cancer (11, 13, 25). Additionally, a large proportion of primary breast tumors that exhibit overexpression of Wip1 also have high expression of ERalpha (12). Indeed, Han et al. showed that Wip1 is regulated by ERalpha. They found that ERalpha binds to the promoter region of PPM1D and treatment of MCF-7 cells with 17beta-estradiol (E2) and ectopic expression of ERalpha increased Wip1 expression levels (Figure 1 and Figure 2) (26). Furthermore, Wip1 has been shown to increase the activity of several nuclear hormone receptors, most likely by enhancing their association with Nuclear Receptor Coactivator-1 (NCOA1), NCOA2 or NCOA3 (27). Recent work has demonstrated that Wip1 induction by E2 and ERalpha promotes cell cycle progression and cell proliferation, thus establishing a positive feedback loop whereby E2 stimulates ERalpha–dependent induction of Wip1, which then further promotes the upregulation of Estrogen-dependent genes to augment cell proliferation (26). Thus, Wip1 is positively regulated by ERalpha and then elicits pro-tumorigenic effects by enhancing ERalpha signaling in breast cancer cells (26).
