FoxM1 and Mammary Gland Biology: From Drug Resistance to Differentiation

The goal of this work is to better understand the mechanisms by which FoxM1 promotes tumor development and progression. FoxM1 is overexpressed in nearly every tumor type examined. While it was believed that the functions of FoxM1 were limited to promoting proliferation, this view is incomplete. Comparing early grade tumors to late aggressive metastatic tumors shows no difference in rate of proliferation (Hanahan and Weinberg, 2011). Therefore, it seems unlikely that the levels of FoxM1 would be need to be elevated in tumors as they progress. While it is possible that the FoxM1 expression increases indirectly, in response to upstream signaling, we believed this increase is specific and necessary for tumor progression. In breast cancers, FoxM1 is correlated with an undifferentiated tumor type and poor patient prognosis. I worked to identify a mechanism by which FoxM1 promotes the growth and development of high-grade tumors. In this process, we identified FoxM1 as a regulator of GATA-3, a factor highly correlated with estrogen expression. Previous studies showed that GATA-3 is silenced by methylation as tumors advance. We demonstrate that FoxM1 can promote the methylation of the GATA-3 promoter by an Rb dependent mechanism. In addition, this work assigned a novel function to FoxM1, the ability to function as a transcriptional repressor. I was also interested in the ability of FoxM1 to promote resistance to breast cancer treatments, specifically the HER2 targeting antibody Herceptin and the microtubule stabilizer Paclitaxel. From this work we identified FoxM1 as a target in resistant tumors. In addition, we demonstrated that targeting FoxM1 functioned to sensitize cells to treatments. This study indicates that perhaps through targeting FoxM1 it would be possible to administer lower doses of chemotherapeutic agents resulting in less toxicity. The lab has worked to develop a small peptide inhibitor of FoxM1. Using this peptide, we were able to demonstrate that targeting FoxM1 does in fact lead to sensitization of both parental and resistant cell lines to treatment. This work assigns novel functions to FoxM1 and provides rationale for establishing it as a target in aggressive breast tumors.