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

The growth of a significant proportion (>95%) of all human breast cancers is initially dependent upon the presence and activation of an Estradiol (E2)-Estrogen Receptor (ER) complex. Our main goals are the characterization of factors involved in ER-dependent growth of breast cancer cells and the molecular mechanism of action the ER. The identification of "primary" ER target genes is imperative for understanding the function of the ER. However there are only a few candidate genes identified that appear to be under the direct regulation of the ER, much less genes that are associated with cell proliferative activity. Thus my laboratory is involved in the identification and characterization of ER-regulated genes in breast cancer cells. The genes that we are currently studying can be categorized into :

  1. genes involved in oxidative stress response and DNA damage
  2. genes involved in cell cycle progression
  3. genes involved in differentiation vs. tumorigenesis

Along these lines we have identified a novel tumor suppressor, EDG1 that is down-regulated by estrogens. We are currently determining the role of EDG1 and several other genes in estrogen-dependent breast tumor initiation, progression, and metastasis. We are also determining the mechanism of regulation of these target genes by the estrogen receptor. These studies should prove useful in the development of repressors for targeted repression of primary ER-regulated genes intimately involved in estrogen-induced breast cancer development as an alternative to the global repression of estrogen-regulated genes.

To better understand the molecular mechanism of transcriptional activation by estrogen receptors (ERs) we used yeast two-hybrid screening assays to isolate proteins that interact with the estrogen-liganded receptor. Using this method we have identified novel protein factors that selectively modulate ER transcriptional activity. Our identification and characterization of ER-selective corepressors can provide considerable insight as to how one can block ER action in breast cancer cells. ER-selective coactivators which enhance ER activity have also been identified and these should also improve our understanding of estrogen-dependent growth and tumorigenicity of breast cancer cells. Along these lines we have identified a novel coactivator, ERCoA3, that may be an important factor in the development of an important clinical problem, tamoxifen resistance. We are conducting studies to elucidate the molecular mechanisms and structural basis behind the effects of ER-selective coregulators on ER-mediated transcription. In addition, functional assays are underway to determine the relevance of these proteins in estrogen-mediated breast tumor growth. These coregulators will be used to elucidate which estrogen-dependent activities are altered when ER-dependent growth is blocked or stimulated, and therefore by what means estrogens regulate the growth of breast cancer cells.

In summary we have a comprehensive research program with two major goals:

  1. characterize the tumor growth regulatory pathways controlled by estrogens
  2. identify novel ways of repressing these pathways

We use a wide variety of approaches including DNA microarray analysis, molecular biology, cell biology, and animal studies (transgenic and knockout) to achieve these goals. Together these studies have important implications for future therapeutic strategies.

 

Selected References:

Wittmann BM, Fujinaga K, Deng H, Ogba N, Montano MM . The breast cell growth inhibitor, Estrogen Down-regulated Gene 1 (EDG1), modulates a novel functional interaction between Estrogen Receptor Alpha and transcriptional elongation factor Cyclin T1. Oncogene in press

Bianco NR, Chaplin L, Montano MM . Differential induction of quinone reductase by phytoestrogens and protection against estrogen-induced DNA damage. Biochemical Journal in press

Montano MM , Deng H, Liu M, Sun X, Singal R. 2004 Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications. Oncogene 23:2442-2453

Wittmann BM, Wang N, Montano MM. 2003. Identification of a novel inhibitor of cell growth that is down-regulated by estrogens and decreased in breast tumors. Cancer Research. 63: 5151-5158

Bianco NR, Perry G, Smith MA, Templeton DJ, Montano MM. 2003 Functional implications of antiestrogen induction of quinone reductase: inhibition of estrogen-induced DNA damage. Molecular Endocrinology. 17:1344-1355

Bianco NR and Montano MM. 2002. Transcriptional regulation of Prothymosin alpha gene by the Estrogen Receptor: Molecular mechanisms and functional implications. Oncogene. 21:5233-5244

Montano MM , Wittmann, BM, Bianco NR. 2000. Identification and characterization of a novel factor that regulates quinone reductase gene transcriptional Activity. Journal of Biological Chemistry. 275: 34306-34313

Montano MM , Ekena, K, Chang WC, and Katzenellenbogen BS. 1999. An estrogen receptor selective corepressor that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. Proceedings of the National Academy of Sciences. 96: 6947-6952

Montano MM , Jaiswal A, Katzenellenbogen BS. 1998. Transcriptional regulation of the human quinone reductase gene by antiestrogen-liganded estrogen receptor ? estrogen receptor ? via the electrophile/antioxidant response element. Journal of Biological Chemistry. 273: 25443-25449

Montano, MM and Katzenellenbogen BS 1997. Quinone reductase: a unique estrogen receptor-regulated genethat is activated by antiestrogens. Proceedings of the National Academy of Sciences. 94: 2581-2586