FoxM1 and Mammary Gland Biology: From Drug Resistance to Differentiation
thesisposted on 2013-07-12, 00:00 authored by Janai R. Carr
FoxM1 is overexpressed in every tumor type examined including those of reproductive, neurological, and hematological origin. Given the widespread expression of FoxM1 across various tumor types it was generally thought that this was directly related to the ability of FoxM1 to regulate the cell cycle. Yet, it is now apparent that FoxM1 can direct additional cellular processes important in tumor progression. FoxM1 has been identified as an early marker of breast cell transformation. Additionally, high FoxM1 correlates with an undifferentiated tumor phenotype, predicts poor patient survival and metastatic relapse. However, clearly defined mechanisms through which FoxM1 promotes an aggressive mammary tumor phenotype had not been characterized. The focus of this work is on two aspects of FoxM1 biology, the ability to promote a drug resistant phenotype and to inhibit mammary differentiation. We identify a novel function of FoxM1, the ability to act as a transcriptional repressor, which plays an important role in regulating the differentiation of luminal epithelial progenitors. Regeneration of mammary glands with elevated levels of FoxM1 leads to aberrant ductal morphology and expansion of the luminal progenitor pool. Conversely, knockdown results in a shift towards the differentiated state. FoxM1 mediates these effects by repressing the key regulator of luminal differentiation, GATA-3. Through association with DNMT3b, FoxM1 promotes methylation of the GATA-3 promoter in an Rb-dependent manner. This study identifies FoxM1 as a critical regulator of mammary differentiation with significant implications for the development of aggressive breast cancers. Inherent and acquired therapeutic resistance in breast cancer remains a major clinical challenge. In the second portion of this work, we report that FoxM1 overexpression confers resistance to the HER2 monoclonal antibody Herceptin and microtubule-stabilizing drug paclitaxel, both as single agents and in combination. FoxM1 altered microtubule dynamics in order to protect tumor cells from paclitaxel-induced apoptosis. Mechanistic investigations revealed that the tubulin destabilizing protein Stathmin, whose expression also confers resistance to paclitaxel, is a direct transcriptional target of FoxM1. Significantly, attenuating FoxM1 expression by siRNA or an ARF-derived peptide inhibitor increased therapeutic sensitivity. Our findings indicate that targeting FoxM1 could relieve therapeutic resistance in breast cancer.