Monica Montano, Ph.D.
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 :
- genes involved in oxidative stress response and DNA damage
- genes involved in cell cycle progression
- 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:
- characterize the tumor growth regulatory pathways controlled by estrogens
- 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