A major research focus in my laboratory is the identification of factors underlying the hormonal responsiveness of human cancers and to determine how to inhibit growth of hormone responsive cancers (i.e. breast and prostate cancers). My laboratory has now broadened their efforts to the identification of factors in breast and prostate cancer critical in the transition to hormone-independence, resistance to cancer therapeutics, and ability to metastasize. We were one of two laboratories to first identify Hexamethylene bisacetamide (HMBA) Induced Protein 1 (HEXIM1), the main focus of this grant. HEXIM1 was originally identified as Estrogen Down Regulated Gene 1 (EDG1), an Estrogen Receptor interacting and corepressor factor that is downregulated by estrogens. We later determined that HEXIM1 inhibits the growth of hormone responsive cancers, and required for inhibitory actions of antiestrogens and antiandrogens (agents that represent the mainstay in the treatment of hormone responsive breast and prostate cancers).
We also looked outside the "box" of epithelial cells, and elucidated HEXIM1 functions in the context of the mammary microenvironment. Our findings suggest that HEXIM1 is a master inhibitor of tumor derived factors critical for the development of the metastatic niche. Thus, loss of HEXIM1 in early carcinomas may contribute to the progression to metastatic disease, but is therapeutically addressable.
We are exploring the translational potential of HEXIM1 by developing methods for localized and prolonged delivery of HMBA through the use of polymers to upregulate HEXIM1 expression in breast and prostate cancers. We also identified a HMBA derivative, 4a1, that is more potent than its parent compound at upregulating HEXIM1 expression. More recently, we identified a potential new target for HMBA and its derivative that opened up a new lead optimization direction for a group of compounds we now refer to as “HEXIM1 Inducers”
To achieve our research goals my laboratory uses a vast array of techniques. My laboratory has extensive experience in transcriptional regulation, genomic approaches, and the development and use of animal models to validate our mechanistic. I still do benchwork, tissue culture, and animal work, allowing me to participate in and closely monitor the development of research projects.
One of the research focuses in my laboratory is the identification of factors underlying the hormonal responsiveness of human cancers and to determine how to inhibit growth of hormone responsive cancers. We have broadened our efforts to the identification of factors in breast and prostate cancer critical in the transition to hormone-independence, resistance to cancer therapeutics, and ability to metastasize.
Therapeutic Advances and Research Breakthroughs
We have identified a novel tumor suppressor, Hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1), which play a critical role in hormone dependent breast and prostate cancer. We have generated animal models that support the role of HEXIM1 as a tumor suppressor and the inhibition of angiogenesis and metastasis. We have also defined the mechanistic basis for HEXIM1 regulation of mammary and prostate tumorigenesis/angiogenesis/metastasis. We are also involved in collaborative projects with investigators at CWRU to visualize and inhibit tumor growth/vascularization/metastasis and development of strategies to enhance delivery of therapeutic agents to tumors.
It has been proposed by other laboratories that breast tumor initiation is due to DNA damage attributable to a combination of estrogen metabolism and preexisting lesions. We have reported that a novel protein, hPMC2, and Estrogen Receptor beta inhibit estrogen-induced DNA damage and breast cell transformation. Based on this we are proposing that hPMC2 plays a role in the prevention of breast cancer. We also determined that hPMC2 plays a role in the response of cancer cells to cancer chemotherapeutic agents.
Finally we are also examining the role of HEXIM1 in the adult heart. Inducibly expressing HEXIM1 in the heart resulted in features associated with an "athlete's heart" but without prior exercise.
Our studies have the potential to provide new therapeutic strategies, targets, and/or biomarkers for hormone refractory and metastatic breast and prostate cancer. In particular we have developed an approach to upregulate HEXIM1 expression in tumors by local and prolonged delivery of derivatives of a compound that upregulate HEXIM1 expression, Hexamethylene-bis-acetamide (HMBA). Our studies support the potential of HMBA derivatives that we have generated as therapeutic agents for hormone refractory and metastatic cancer.
Our findings in HEXIM1 function in the adult heart indicate that HEXIM1 plays a critical regulatory role in coordinating responses of the adult heart to stress and its reexpression in the adult may be useful in cardioprotection therapy.
Yeh IJ, Song K, Wittmann BM, Bai X, Danielpour D, Montano MM. HEXIM1 plays a critical role in the inhibition of the Androgen Receptor by antiandrogen. Biochem J. 2014 Sep 1;462(2):315-27. doi: 10.1042/BJ20140174.
Zhong B, Lama R, Ketchart W, Montano MM*, Su B*. Lead optimization of HMBA to develop potent HEXIM1 inducers. Bioorg Med Chem Lett. 2014 Mar 1;24(5):1410-3. doi: 10.1016/j.bmcl.2014.01.025. Epub 2014 Jan 17. (*corresponding authors).
Yeh IJ, Ogba N, Welford S, Montano MM. HEXIM1 down-regulates hypoxia-inducible factor-1α protein stability. Biochem J. 2013 Dec 1;456(2):195-204. doi: 10.1042/BJ20130592.
Montano MM, Desjardins C, Doughman YQ, Hsieh YH, Hu Y, Bensinger H, Wang C, Stelzer S, Dick T, Hoit B, Chandler MP, Yu X Watanabe M, Inducible re-expression of HEXIM1 causes physiological cardiac hypertrophy in the adult mouse. Cardiovasc Res. 2013 Jul 1;99(1):74-82. doi: 10.1093/cvr/cvt086. Epub 2013 Apr 11.
Ketchart W, Smith KM, Krupka T, Wittmann BM, Hu Y, Rayman P, Doughman YQ, Albert JM, Bai X, Finke J, Xu Y, Exner AA, Montano MM. Inhibition of metastasis by HEXIM1 through effects on cell invasion and angiogenesis. Oncogene. 32:3829-3839.
Krishnamurthy N, Hu Y, Siedlak S, Doughman YQ, Watanabe W, Montano MM. (2012) Induction of quinone reductase by tamoxifen or DPN protects against mammary tumorigenesis. FASEB J. 26:3993-4002
Krishnamurthy N, Ngam CR, Berdis AJ, Montano MM. (2011) The exonuclease activity of hPMC2 is required for transcriptional regulation of the QR gene and repair of estrogen-induced abasic sites. Oncogene. 30:4731-4739.
Ketchart W, Ogba N, Kresak A, Albert J, Pink J, Montano MM. (2011) HEXIM1 is a critical determinant of the response to tamoxifen. Oncogene 30:3563-3569.
Ogba N, Doughman YQ, Chaplin LJ, Hu Y, Gargesha M, Watanabe M, Montano MM (2010) HEXIM1 modulates vascular endothelial growth factor expression and function in breast epithelial cells and mammary gland. Oncogene 29:3639-49.
Ogba N, Chaplin LJ, Doughman YQ, Fujinaga K, Montano MM. (2008) HEXIM1 regulates E2/ERalpha-mediated expression of Cyclin D1 in mammary cells via modulation of P-TEFb. Cancer Research 68: 7015-7024.
Montano MM, Doughman YQ, Deng H, Chaplin L, Yang J, Wang N, Zhou Q, Ward N, Watanabe M. (2008) Mutation of the HEXIM1 gene results in defects during heart and vascular development partly through downregulation of VEGF. Circulation Research. 102: 415-422.