Pharmacology & Cancer Biology | Duke University Medical Center

Dr. Donald McDonnell

Donald P. McDonnell, Ph.D.
Professor of Pharmacology and Cancer Biology
Glaxo-Wellcome Professor of Molecular Cancer Biology
Director of Graduate Studies, Pharmacology

Duke University Medical Center
C259 LSRC
Box 3813
Durham, NC 27710

Phone: 919-684-6035
E-mail: donald.mcdonnell@duke.edu

Research Interests

The steroid hormones estrogen and progesterone are potent humoral effectors involved in development and maintenance of mammalian reproductive function. These hormones mediate their cellular effects through specific intracellular receptors located within target cell nuclei. The steroid receptors are latent transcription factors which upon interaction with their cognate ligand are activated and have the potential to alter the rate of transcription of specific target genes. The number of diseases associated with inappropriate production or responses to hormonal stimuli highlights the medical and biological importance of these effectors. Both estrogen and progesterone have been implicated in a variety of hormone dependent cancers of the breast, ovary and endometrium. In addition, the onset of post-menopausal osteoporosis is related to a decrease in production of estrogen. Specifically, our laboratory is interested in defining the role of estrogen and progesterone in the pathology of hormone dependent breast cancers and how this can be modulated by compounds which oppose the action of these steroids. To this end, we are using molecular, biochemical and genetic approaches to define the individual steps in steroid hormone receptor signaling pathways which function in breast cancer cells. It is anticipated that this information will lead to an understanding of the pharmacology of estrogen and progesterone in normal breast and how cellular responsiveness to these hormones is altered in breast cancer. It is likely that the insights gained from these studies will facilitate the development of novel therapeutically important molecules for the treatment of breast cancer and other important endocrinopathies.

Publications

Connor, C.E., Norris, J.D., Broadwater, G., Willson, T.M., Gottardis, M.M., Dewhirst, M.W. and McDonnell, D.P. (2001) Circumventing tamoxifen resistance in breast cancers with GW5638, an antiestrogen that induces a unique conformational change in the estrogen receptor. Cancer Res. 61: 2917-2922.

Chang, C.-Y., Walther, P.J. and McDonnell, D.P. (2001) Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer. Cancer Res. 61: 8712-8717.

Chang, C.-Y. and McDonnell, D.P. (2002) Evaluation of ligand-dependent changes in androgen receptor structure using peptide probes. Mol. Endocrinol. 16: 647-660.

Li, X., Kimbrel, E.A., Kenan, D.J. and McDonnell, D.P. (2002) Direct interactions between corepressors and coactivators permit the integration of nuclear receptor-mediated repression and activation. Mol. Endocrinol. 16: 1482-1491.

McDonnell, D.P. and Norris, J.D. (2002) Connections and regulation of the human estrogen receptor. Science 296: 1642-1644.

Jansen, M.S., Nagel, S.C., Miranda, P.J., Lobenhofer, E.K., Afshari, C.A. and McDonnell, D.P. (2004) Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc. Natl. Acad. Sci. 101: 7199-7204.

Wu, Y.-L., Yang, X., Ren, Z., McDonnell, D.P., Norris, J.D., Willson, T.M. and Greene, G.L. (2005) Structural basis for an unexpected mode of SERM-mediated ER antagonism. Mol. Cell 18: 413-424.

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