Wilms' Tumor 1 (WT1) as a Novel Molecular Target in Breast Cancer

Abstract

Abstract : High levels of Wilms' Tumor 1 (W%T1) mRNA in breast tumors are linked with poor prognosis for breast cancer patients. However, the function of WT1 protein in breast cancer is not known. Recently we demonstrated that the HER2/neu oncogene, which is a well-known poor prognostic indicator for breast cancer patients, engages Akt to increase WT1 expression to stimulate G1 to S phase cell cycle progression and suppress apoptosis in breast cancer cells. Increased G1 to S phase cell cycle progression and decreased apoptosis are correlated with increased cyclin D1 and Bcl-2 levels. We have preliminary data indicating that Insulin-like Growth Factor-I also uses the Akt pathway to increase WT1 protein expression. We are currently investigating the role of WT1 in Insulin-like Growth Factor-I signaling. WT1 has been shown to undergo two splicing events, which result in four different isoforms. Our preliminary data indicate that all four WT1 isoforms enhance the proliferation of MCF-7 breast cancer cells, and reduce their sensitivity to tamoxifen. However, the WT1 isoforms do not appear to modulate the sensitivities of MCF-7 cells to doxorubicin and taxol. We plan to determine the mechanisms and the isoforms by which WT1 deregulates breast cancer cell proliferation and tamoxifen sensitivity.