FoxM1 in tumor cell

Jesse Brown Va Medical Center, Chicago IL

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Abstract

Summary/Abstract Background and Innovation: Metastatic breast cancer is the major cause of cancer related deaths in women worldwide. Despite improvement in the disease-management, patients become resistant to the available therapies. Clearly, there are major gaps in our understanding of the mechanisms by which metastatic breast cancer cells evolve and escape therapy. This proposal focuses on FoxM1 whose overexpression coincides with metastatic progression as well as resistance to therapies. FoxM1 is both a transcriptional activator and a repressor. It activates cell-proliferation genes through its interaction with the coactivator CBP, and it represses differentiation genes through a retinoblastoma protein (Rb)- dependent interaction with DNMT3b. To obtain insights into the mechanism of FoxM1-driven metastasis, we dissected the activator/repressor functions, specifically to determine the role of the repression function because it involves a targetable enzyme, DNMT3b. We characterized a mutant FoxM1 that harbors point mutations in the activation domain, allowed binding to the coactivator CBP, but not to Rb and DNMT3b. Using CRIPR/Cas9, we have generated a novel knock-in mouse line that expresses the mutant FoxM1, which is activator only and deficient in the repression function. Female mice expressing the repression-deficient mutant of FoxM1 exhibit lactation deficiency. Moreover, MMTV- PyMT driven mammary tumors in the FoxM1-mutant mice are deficient in lung metastasis. The impairment in metastasis is related to deficiencies in the stem/progenitor types of pro-metastatic tumor cells. In this proposal, we will focus on the Rb-dependent FoxM1/DNMT3b interaction to determine how that interaction supports the stem/progenitor-like tumor cells and investigate whether similar mechanisms are involved in sustenance of the normal mammary stem/progenitor cells. Also, FoxM1 is overexpressed in the Her2+ breast cancers, and it confers resistance to anti-Her2/paclitaxel. We will investigate the hypothesis that the Rb-dependent FoxM1/DNMT3b interaction is involved in the metastasis and resistance of the Her2+ breast cancers. Significance and Impact to Veterans Healthcare: Metastatic breast cancer is a challenging problem among the women US veterans. A recent study by the Walter Reed Army Medical Center indicated that women veterans are 40% more likely to develop breast cancer compared to their civilian counterparts. The current proposal will establish a role of the FoxM1/Rb/DNMT3b interaction in metastasis and drug-resistance. That is significant because a large population of the luminal type as well as the Her2+ breast cancer patients are Rb+ and express FoxM1 at high-levels. Our studies using pre-clinical models will develop scientific rationale for determining whether the FoxM1-hi/Rb+ patients would benefit from including FDA-approved DNMT-inhibitors in their therapy. Path to translation/implementation: The repression function of FoxM1 and the interactions with Rb/DNMT3b were discovered with previous Merit grants. During the last funding period, we generated a novel mouse model and demonstrated significant roles of the repression mechanism of FoxM1 in breast cancer metastasis. Current proposal will establish how the FoxM1/Rb/DNMT3b interaction drives metastasis and drug resistance of the Rb+ tumors. Also, the proposed studies will determine whether DNMT-inhibitors inhibit the pro-metastatic tumor cells by disabling the repression function of FoxM1 – That is significant because DNMT-inhibitors are approved for cancer therapy. In the next phase, we will investigate whether the FoxM1-mechanisms of metastasis and drug resistance, identified in the pre-clinical models, are active in aggressive Rb+/FoxM1-hi human cancers, which will inform refining breast cancer patient selection for therapy by including DNMT-inhibitors.