department of pharmacology

Monica Montano, Ph.D.

Montano

Associate Professor

Phone: (216) 368-3378
Fax: 216-368-1300
E-mail: monica.montano@case.edu
W305B Wood Building

Research
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.

Applications
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.

Relevant Publications:
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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
  7. 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.
  8. 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 reexpression of HEXIM1 activates a physiological rather than a pathological response in the adult heart. Cardiovascular Research. 99:74-82.
  9. Yeh IJ, Ogba N, Welford S, Montano MM. HEXIM1 downregulates HIF-1alpha protein stability. Biochemical Journal 456:195-204.
  10. Zhong B, Lama R, Ketchart W, Montano MM*, Su B*. Lead optimization of HMBA to develop potent HEXIM1 inducers. accepted Bioorganic & Medicinal Chemistry Letters. 24:1410-1413. (*corresponding authors).
  11. 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. Biochemical Journal. In press