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Donald McDonnell

Glaxo-Wellcome Professor of MCB and Chair
Pharmacology and Cancer Biology
(919) 684-6035
Research Interest: 
Signal transduction
Research Summary: 
Identification of druggable targets within estrogen- and androgen-regulated signal transduction pathways that can be exploited in the development of novel breast and prostate cancer therapeutics.
Research Description: 

The nuclear receptor superfamily of ligand-regulated transcription factors are the targets of drugs that account for over 20% of all prescriptions written. Within this family of over 40 proteins are receptors that enable cells to respond to steroid hormones, thyroid hormone, retinoids and vitamin D. Also contained in this family are several “orphan receptors” for which specific hormones remain to be identified. The research in our laboratory is focused on defining the mechanism of action of those nuclear receptors whose expression and/or activity is implicated in the pathogenesis of breast and prostate cancer. We have a specific interest in defining the signaling pathways in these cancers in which the estrogen, progesterone and androgen receptors are engaged. It is anticipated that, by targeting critical steps in the signaling pathways of these receptors, molecules with new mechanisms of action can be developed that are likely to be more effective than existing drugs of this class. Furthermore, we have recently determined that the orphan nuclear receptor, Estrogen Related Receptor-alpha (ERR alpha), is required for the growth and metastasis of breast cancer cells, making it a target of high priority for our group. Projects ongoing in the laboratory range from the most fundamental, where an understanding of the mechanism(s) by which nuclear receptors regulate gene transcription is the goal, to the very applied, where the development of novel pharmaceuticals is the desired endpoint.

The metabolic regulator ERRα, a downstream target of HER2/IGF-1R, as a therapeutic target in breast cancer.
Chang CY, Kazmin D, Jasper JS, Kunder R, Zuercher WJ, McDonnell DP.
Cancer Cell. 2011. 20:500-10.

The homeodomain protein HOXB13 regulates the cellular response to androgens.
Norris JD, Chang CY, Wittmann BM, Kunder RS, Cui H, Fan D, Joseph JD, McDonnell DP.
Mol Cell. 2009. 36:405-16.

The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors.
Nelson ER, DuSell CD, Wang X, Howe MK, Evans G, Michalek RD, Umetani M, Rathmell JC, Khosla S, Gesty-Palmer D, McDonnell DP.
Endocrinology. 2011. 152:4691-705.

WNT11 expression is induced by estrogen-related receptor alpha and beta-catenin and acts in an autocrine manner to increase cancer cell migration.
Dwyer MA, Joseph JD, Wade HE, Eaton ML, Kunder RS, Kazmin D, Chang CY, McDonnell DP.
Cancer Res. 2010. 70:9298-308.

CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells.
Frigo DE, Howe MK, Wittmann BM, Brunner AM, Cushman I, Wang Q, Brown M, Means AR, McDonnell DP.
Cancer Res. 2011. 71:528-37.