Irina Budunova, MD, PhD
Associate Professor of Dermatology
Biography
Dr. Irina Budunova is an Associate Professor of Dermatology at Northwestern. She received her medical degree from N.N. Pirogov Medical Institute in Moscow and her Ph.D. in experimental Oncology from the Department of Chemical Carcinogenesis of the National Cancer Research Center in Moscow, where she served as a Scientist until emigrating to the Unites States in 1992. She became a faculty member at MD Anderson Cancer Center in Houston and later at the AMC Cancer Research Center in Denver. She moved to Northwestern as an Associate Professor of Dermatology in 2003. She is an expert on cell gap junctions, carcinogenesis and glucocorticoids receptors, and has published approximately 50 papers and chapters on these subjects.
Research Interests
Dr. Budunova’s research interests include alteration of cell signaling during tumorigenesis as the basis for the development of new approaches to prevention and treatment of cancer. Her current projects are centered on the role of the glucocorticoid receptor (GR) and its cross-talk with other transcription factors including the key anti-inflammatory and anti-apoptotic factor NF-kB, in skin and prostate tumor formation. She is also interested in the role of GR signaling in the maintenance of skin stem cells and in the role of stem cells in skin cancer resistance.
1. Tumor suppressor effect of GR in skin: implication of stem cells.
The effects of glucocorticoids are mediated by the glucocorticoid receptor (GR) that regulates gene expression by (i) transactivation that requires GR binding to gene promoters and (ii) transrepression mediated via negative interaction between GR and other transcription factors. Using Keratin5. GR transgenic animals, we found that GR acts as a tumor suppressor in skin and that the transrepression is especially important for GR-mediated inhibition of skin tumor development. The target cells for skin carcinogenesis are epithelial stem cells localized in the hair follicles. We discovered a novel mechanism for GR tumor suppressor effect through the down-regulation of the number and proliferative potential of these stem cells.
We are currently looking for factors/signals that trigger proliferation of follicular skin stem cells in skin during carcinogenesis, and will study the cross-talk between GR and these signals. We will also study the role of GR transrepression in skin carcinogenesis and in stem cell maintenance using pharmacological and genetic approaches including our new model - K5.GRdim mice expressing mutant GR that mediates mostly GR transrepression.
2. Tumor suppressor effect of GR in prostate.
Glucocorticoid hormones are extensively used for combinational chemotherapy of patients with advanced prostate cancer (PC). Despite the wide use of glucocorticoids in the clinic, very little was known about the expression and function of GR in PC cells and tumors. Our recent results indicated that GR acts as a tumor suppressor in prostate. GR expression was strongly decreased/lost in epithelial cells in ~ 80% of prostate cancers and this loss occurred early, at the stage of precancerous lesions. The introduction of GR into prostate cancer cells lacking the endogenous receptor, resulted in dramatic inhibition of their growth, and “normalization” of their phenotype. In prostate cells GR inhibited activity of numerous transcription factors supporting our hypothesis that tumor suppressor effect of GR is mediated via transrepression. We will continue to study the role of GR-induced gene transrepression in prostate tumorigenesis using novel transgenic mouse models and pharmacological approaches.
3. Novel selective GR activators (SEGRA) as potential anti-cancer and anti-inflammatory drugs with reduced side effects.
Glucocorticoids are among the most effective anti-inflammatory agents and also used for combinational chemotherapy. However, patients inevitably develop resistance to steroids along with numerous side effects. While GR transrepression is the leading mechanism of anti-inflammatory and anti-cancer therapeutic effects of glucocorticoids, many adverse effects are mediated by GR transactivation. Thus, “dissociated” GR ligands that specifically activate GR transrepression hold a great potential for the treatment of patients with inflammatory and hyperproliferative skin diseases as well as for cancer treatment.
We and others have recently identified a novel GR ligand called Compound A (CpdA). CpdA is a synthetic analog of a compound from Namibian shrub; it prevents GR-DNA binding, and shifts GR activity towards transrepression. Importantly, CpdA has reduced side effects in vivo, and in comparison to glucocorticoids does not induce tachyphylaxis (acquired resistance) during the treatments.
Current directions of our research are to delineate mechanisms of CpdA effects in skin and prostate. We are also focused on the mechanisms that regulate GR stability and are important for prevention of acquired resistance to glucocorticoids.
