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Irina V. Budunova, MD, PhDAssociate Professor
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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 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.
Glucocorticoids affect cellular functions via the glucocorticoid receptor (GR), a well known transcription factor. Using Keratin5.GR transgenic animals that express increased amount of spontaneously activated GR in basal keratinocytes in skin, we showed that GR acts as a tumot supressor gene during skin carcinogenesis. My laboratory discovered a novel mechanism for the tumor suppressor effect of the GR: through the regulation of the number and status of skin epithelial stem cells localized in the hair follicles. We found that the number of follicular stem cells in the skin of K5.GR transgenic mice was significantly decreased, and that GR overexpression resulted in the decreased proliferative potential and survival of follicular epithelial stem cells and diminished their “stemness” by altering the expression of stem cell markers. Using transcriptional profiling of skin tumors from wild type and GR transgenic animals, we discovered that the mechanisms underlying the anti-inflammatory and tumor suppressor effects of GR are similar. These mechanisms are collectively called transrepression and involve negative interaction between GR and other transcriptional factors.
My laboratory also found that normal follicular epithelial stem cells highly express GR and are very sensitive to the growth inhibitory effects of glucocorticoids. Overall these novel findings show that GR signaling plays an important role in the maintenance of skin stem cells. In addition, they position glucocorticoids as important physiological and pharmacological regulators of epidermal homeostasis.
In the future we plan to identify the factors/signals that trigger proliferation of follicular skin stem cells in skin treated with tumor promoters, and to 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 novel transgenic models and pharmacological approaches.
In addition, we are very much interested in the role of GR in development. We found that GR overexpression resulted in the inhibition of large cluster of important developmental genes specifically in stem cells. This correlates well with the strong developmental abnormalities of skin, hair, oral cavity and ocular structures found in K5.GR mice.
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 supressor in prostate. GR expression was strongly decreased/lost in epithelial cells in ~ 80% of prostate cancers and this loss occured 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 including AP-1, NF-kB, p53, Ets-1, Elk-1, STAT1 supporting our hypothesis that tumor suppressor effect of GR is mediated via transrepression. GR also inhibited function of androgen receptor – a key player in prostate cancer development. 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 modulators (SGRM) as potential anti-cancer drugs.
The GR is a transcription factor that regulates gene expression by DNA-binding dependent transactivation and by DNA-binding-independent transrepression through negative interaction with other transcription factors. It is currently well accepted that the anti-inflammatory therapeutic effects of glucocorticoids are mostly mediated via gene transrepression, while the many side effects of glucocorticoids are mediated via DNA-dependent transactivation. Our recent studies revealed the leading role of GR-mediated gene repression during the inhibition of prostate and skin cancer cell growth. These are important novel observations, as they imply that the anti-inflammatory and anti-cancer effects of GR signaling occur by similar mechanisms. Currently many leading pharmaceutical companies in U.S. and Europe are conducting an intensive search for selective GR modulators that preferentially induce GR transrepression aimed at the development of novel generation of anti-inflammatory drugs with improved therapeutic: side effect ratio. Our findings may have important future clinical applications for selective GR modulators for skin and prostate cancer prevention and treatment.
Our laboratory is now focused on the study of novel modulators of steroid hormone receptors that mostly induce GR-mediated gene transrepression. The long-term goals of this project are to determine the effect of selective GR modulators on stem cell maintenance in skin; to test their anti-cancer effect in vivo in skin and in prostate; to define the leading molecular mechanisms underlying their apoptotic and growth inhibitory effects in cancer cells.
4. Role of up-stream IkB kinases (IKKs) and NF-kB transcriptional factor in prostate tumorigenesis.
One of the contributing factors to high mortality rate from prostate cancer is the extreme resistance of PC cells to apoptosis induced by radio- and chemotherapy. One of the central anti-apoptotic pathways in cells is mediated by NF-kB transcription factor. We found that NF-kB is activated in androgen-independent prostate cancer cells due to constitutive activation of upstream IKK kinases important for degradation of IkB inhibitory proteins. We are actively involved in the studies focused on the specific role of different IKKs including IKKa, IKKβ, and IKKi in prostate cancer development, cross-talk between steroid hormone receptors such as GR and androgen receptor (AR) with NF-kB. We are also testing the effect of different classes of pharmacological inhibitors of NF-kB, including IKK inhibitors, proteasome inhibitors, and non-steroidal ligands of GR on PC cell growth and apoptosis. The goals of these studies is the application of NF-kB targeting as an approach for treatment of prostate cancer in men.
Budunova, I.V., Perez, P., Vaden, V.R., Spiegelman, V.S., Slaga, T.J., Jorcano, J.L. Increased expression of p50-NF-kB and constitutive activation of NF-kB transcription factors during mouse skin carcinogenesis. Oncogene, 18:7423-7431, 1999.
Perez, P., Page, A., del Rio, M., Bravo, A., Gimenez-Conti, I., Budunova, I., Slaga, T., and Jorcano, J. The proliferative and inflammatory responses are impaired in the skin of transgenic mice overexpressing the glucocorticoid receptor. FASEB Journal, 11:2030-2032, 2001.
Gasparian, A.V., Yao, Y., Kowalczyk, D., Lyakh, L. A., Karseladze, A., Slaga, T.J.,and Budunova, I.V. Mechanisms of constitutive NF-kB activation in prostate carcinoma cells. Journal of Cell Science, 115: 141-151, 2002.
Gasparian, A.V., Yao, Y.J, Lu, J., Slaga T.J, and Budunova, I.V. Selenium compounds inhibit IkB kinase and transcriptional factor NF-kB in prostate cells. Molecular Cancer Therapeutics, 1(12):1079-1087, 2002.
Budunova, I.V., Kowalczyk, D., Yao Y.J., Perez., P., Jorcano, J.L., Slaga, T.J. Glucocorticoid receptor is the potent suppressor of mouse skin carcinogenesis. Oncogene, 22:3279-3287, 2003.
Yemelyanov A., Gasparian A., Lindholm P., Dang L., Pierce J., F. Kisseljov, A. Karseladze, Budunova I. Effect of IKK inhibitor PS1145 on NF-kappaB function, proliferation, apoptosis, and invasion activity in prostate carcinoma cells. Oncogene, 25(3):387-98, 2006.
Yemelyanov A., Czwornog J., Chebotaev D., Karseladze A., Kulevitch E., Yang X., Budunova I. Tumor suppressor effect of glucocorticoid receptor in prostate. Oncogene, 26:1885-1896, 2007.
Chebotaev D, Yemelyanov A, Zhu L, R. M. Lavker RM, and Budunova I. The tumor suppressor effect of the glucocorticoid receptor in skin is mediated via its effect on follicular epithelial stem cells. Oncogene. 26(21):3060-3068, 2007.
Chebotaev D, Yemelyanov A., Yao Y.J., Lavker R.M., and Budunova I. Epithelial cells in the bulge region of the hair follicle do not contribute to epidermal regeneration after glucocorticoid-induced cutaneous atrophy. J. Invest. Dermatology, Jul 26; [Epub ahead of print], 2007
Chebotaev D., Yemelyanov A., and Budunova I. The mechanisms of tumor suppressor effect of glucocorticoid receptor in skin. Mol Carcinogenesis 46:732-740, 2007.
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View Publications by Irina Budunova listed in the National Library of Medicine (PubMed). |
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