Breast cancer remains one of the deadliest diseases in women. According to American Cancer Society about 230,480 women in the US were diagnosed with invasive breast cancer in 2011 and about 40,000 died in that year. Also, a 2009 study by the Walter Reed Army Med. Ctr. suggested that women in the army are 20-40% more likely to develop breast cancer. Therefore, a greater understanding of breast cancer and better therapeutic strategies are urgently needed. This proposal focuses on the fork-head box transcription factor FoxM1 that is over-expressed in the aggressive forms of breast cancers, including the Basal type(s) of breast cancer. Moreover, over-expression of FoxM1 coincides with metastasis and is a biomarker for poor prognosis. In this proposal, we plan to evaluate the functions of FoxM1 in normal mammary gland as well as in the mechanisms that lead to the development of aggressive breast cancer. In addition, we will determine whether targeting FoxM1 using a specific peptide-inhibitor inhibits metastatic progression of breast cancer. The proposal is based on a newly discovered function of FoxM1 in repression of GATA-3 in mammary gland. FoxM1 is expressed at a high level in the luminal progenitor cells. GATA-3 induces differentiation of those progenitors. We will test the hypothesis that FoxM1 controls excessive differentiation during pregnancy, and thus plays an important role in maintaining plasticity of the mammary gland. GATA-3 also is a suppressor of metastasis in breast cancer. Therefore, we will investigate the hypothesis that the repression function of is critical to the mechanism by which FoxM1 contributes to the development of highly aggressive breast cancer. We have characterized a highly specific peptide inhibitor of FoxM1 derived from the tumor suppressor p19ARF that in a cell- penetrating form (ARF-peptide) inhibits metastatic colonization of liver cancer, p53-null sarcoma and p53-null lymphoma. We will investigate whether that peptide-inhibitor efficiently blocks metastatic progression and/or sensitizes breast cancers to available therapies, such as Taxol.
The specific aims are:
Aim1 : Investigate the roles of FoxM1 in mammary gland.
Aim2 : Investigate the roles of FoxM1 in the metastatic progression of breast cancer.
Aim3 : Investigate whether the ARF-derived peptide inhibitor of FoxM1 inhibits mammary tumor progression. This merit review proposal is in response to BLR&D RFA on Women's Health. As more women are entering the US Army, health care at the VA with regards to invasive breast cancer is becoming increasingly significant. Our studies will investigate several novel hypotheses, which will be insightful in understanding and in therapy of metastatic breast cancers.
Invasive breast cancer is becoming a significant health problem as more women are entering US Army. A 2009 study by the physicians at the Walter Reed Army Medical Center indicated that women in the army are 20 to 40% more prone to development of breast cancer compared to the same non-army age group. This proposal focuses on the FoxM1 gene that is over-expressed in high-grade breast cancer. Studies in this proposal will reveal the mechanism by which FoxM1 contributes to the development of the high-grade breast cancer. In addition, the studies will determine whether targeting FoxM1 inhibits high-grade progression of breast cancer.
| Kopanja, Dragana; Huang, Shuo; Al Raheed, Mohamed Rizwan Haroon et al. (2018) p19Arf inhibits aggressive progression of H-ras-driven hepatocellular carcinoma. Carcinogenesis 39:318-326 |
| Mukhopadhyay, Nishit K; Chand, Vaibhav; Pandey, Akshay et al. (2017) Plk1 Regulates the Repressor Function of FoxM1b by inhibiting its Interaction with the Retinoblastoma Protein. Sci Rep 7:46017 |
| Fantini, Damiano; Huang, Shuo; Asara, John M et al. (2017) Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2. Mol Biol Cell 28:192-200 |
| Huang, Shuo; Fantini, Damiano; Merrill, Bradley J et al. (2017) DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer. Cancer Res 77:6562-6575 |
| Kopanja, Dragana; Raychaudhuri, Pradip (2016) TGF? signaling: a friend or a foe to hepatic fibrosis and tumorigenesis. Ann Transl Med 4:122 |
| Kopanja, Dragana; Pandey, Akshay; Kiefer, Megan et al. (2015) Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features. J Hepatol 63:429-36 |
| Wang, Zebin; Zheng, Yu; Park, Hyun Jung et al. (2013) Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma. Mol Cancer Ther 12:759-67 |
| Carr, Janai R; Kiefer, Megan M; Park, Hyun Jung et al. (2012) FoxM1 regulates mammary luminal cell fate. Cell Rep 1:715-29 |
| Park, Hyun Jung; Gusarova, Galina; Wang, Zebin et al. (2011) Deregulation of FoxM1b leads to tumour metastasis. EMBO Mol Med 3:21-34 |
| Wang, Zebin; Park, Hyun Jung; Carr, Janai R et al. (2011) FoxM1 in tumorigenicity of the neuroblastoma cells and renewal of the neural progenitors. Cancer Res 71:4292-302 |
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