Wilms' Tumor 1 Suppressor Gene Mediates Antiestrogen Resistance via Down-Regulation of Estrogen Receptor-α Expression in Breast Cancer Cells

Abstract

The antiestrogen tamoxifen has been used in the treatment of hormone-responsive breast cancer for over a decade. The loss of estrogen receptor (ER) expression is the most common mechanism for de novo antiestrogen resistance. Wilms' tumor 1 suppressor gene (WT1) is a clinically useful marker that is associated with poor prognosis in breast cancer patients; its high level expression is frequently observed in cases of breast cancer that are estrogen and progesterone receptor negative. The lack of expression of these receptors is characteristic of tumor cells that are not responsive to hormonal manipulation. To determine whether there is a linkage between WT1 expression and antiestrogen resistance in breast cancer cells, we studied the effect of WT1 on tamoxifen responsiveness in ERA-positive MCF-7 cells. We found that overexpression of WT1 in MCF-7 markedly abrogated tamoxifen-induced cell apoptosis and 17B-estradiol (E 2 ) -mediated cell proliferation. The expressions of ERA and its downstream target genes were significantly repressed following overexpression of WT1, whereas the down-regulation of WT1 by WT1 shRNA could enhance ERA expression and the sensitivity to tamoxifen treatment in ERA-negative MDA468 and HCC1954 cells that express high levels of WT1. Furthermore, we have confirmed that the WT1 protein can bind to endogenous WT1 consensus sites in the proximal promoter of ERA and thus inhibit the transcriptional activity of the ERA promoter in a WT1 site sequence -specific manner. Our study clearly implicates WT1 as a mediator of antiestrogen resistance in breast cancer through down-regulation of ERA expression and supports the development of WT1 inhibitors as a potential means of restoring antiestrogen responsiveness in breast cancer therapy.

High Wilms’ tumor 1 mRNA expression correlates with basal-like and ERBB2 molecular subtypes and poor prognosis of breast cancer

“…Though Miyoshi et al (18) found that the prognosis of patients with high WT1 expression was significantly worse than that in patients with low WT1 expression, Camcı et al failed to confirm this finding in a later study (23). In the present study, we concluded that WT1 mRNA high expression predicted poor prognosis of breast cancer patients when using 3.1 as cutoff value, which might be due to the facts that WT1 could promote proliferation, invasion, migration, response to hypoxia and drug resistance of cancer cells (19)(20)(21)(22)35,37,38).…”

“…In this study, we found that WT1 expression was higher in ER-negative patients than in ER-positive patients, which may be explained by the fact that overexpression of WT1 directly resulted in the down-regulation of ER expression (22). In addition, our results also demonstrated that WT1 tended to be overexpressed in tumors with high histological grades.…”

“…Therefore, it is necessary to clarify the oncogenic or tumor suppressive role of WT1 in breast cancer. Moreover, relationship between WT1 expression and clinicopathological parameters and prognosis of breast cancer was inconsistent so far (12,18,22,23), and the possible correlation between WT1 expression and molecular subtypes has not been reported.…”

WT1 expression in breast cancer disrupts the epithelial/mesenchymal balance of tumour cells and correlates with the metabolic response to docetaxel

“…Also, WT1 expression is significantly higher in ER-positive (luminal) than in ER-negative (basal) tumours. This finding may be of particular interest, given that WT1 has been shown to both interact with ERα and modulate its expression in vitro 55.…”

Detection of Expressional Changes Induced by Intrauterine Growth Restriction in the Developing Rat Mammary Gland via Exploratory Pathways Analysis

“…The cell type, its current state of development [61] and the ratio of WT1 isoform expression [62] may be crucial for WT1 to either promote or suppress tumor development. On the other hand, mammary tumors with high levels of WT1 have a poor prognosis and high levels of WT1 expression are frequently observed in cases of breast cancer that are estrogen and progesterone receptor negative [63]. WT1 expression is regulated by progesterone in a tissue dependent manner.…”