Dale Buck Hales, Ph.D.
Professor and Chair
Southern Illinois University School of Medicine
Dietary intervention in the prevention and treatment of Ovarian cancer
Inflammation and oxidative stress contribute to numerous pathologies including cancer and decreased reproductive health. Our studies examine the mechanisms through which immune-endocrine interactions control steroid hormone biosynthesis, metabolism and action; affect mitochondrial function; and contribute to hormonal carcinogenesis.
Ovarian cancer is the leading cause of death from gynecological malignacies due to the late stage at which it is usual detected. The lack of suitable animal models have hampered progress in ovarian cancer, because with the exception of the laying hen no other animals are inflicted with spontaneous ovarian surface epithelial (OSE) cancer that replicates the human disease. Using the chicken as a model for ovarian cancer our studies examine the role of inflammation and oxidative stress resulting from ovulation and constant remodeling of the OSE in the malignant transformation of the tissue. A goal of these studies is to develop functional food based dietary intervention with omega-3 fatty acids/flax seed chemoprevention. Visit the CancerChix Blog, http://cancerchix.blogspot.com/ An informal and lay level discussion of research on Ovarian Cancer conducted in the laying hen, Gallus Domesticus. The blog also discusses current topics relevant to cancer including chemoprevention, dietary intervention, natural products and theories on the cause and hope for the cure of cancer.
Inflammatory disease and chronic infection are known to be associated with decreased reproductive health. One mechanism through which activation of the immune-system adversely affects the reproductive capacity of affected individuals is by perturbation of gonadal steroid biosynthesis. Testosterone production by testicular Leydig cells is crtical for reproductive function and health and vitality of the male. Our studies have shown that following induction of experimental endotoxemia there is a biphasic inhibition of testosterone production. There is an acute inhibition due to reactive oxygen mediated perturbation of Leydig cell mitochondria, resulting in a rapid post-translational inhibition of Steroidogenic Acute Regulatory (StAR) protein, and a prolonged,cytokine-mediated transcriptional repression of the steroidogenic enzyme gene expression, in paticular the expression of CYP17 (P450c17).
Community of Science (COS) curriculum vitae
Publications from the Hales laboratory
Held Hales, K., Diemer, T., Ginde, S., Roberts, M.R., Shankar, B.K., Bosmann, H.B, Hales, D.B . “Diametric effects of bacterial endotoxin lipopolysaccharide on adrenal and Leydig cell Steroidogenic Acute Regulatory Protein (StAR).” Endocrinology 141:4000-4012 (2000).
Diemer, T., Hales, D.B ., Weidner. W. “Immune–endocrine interactions and Leydig cell function: the role of cytokines.” Andrologia 35:55–63 (2003 )
Diemer, T., Allen, J.A., Held Hales, K., Hales, D.B. “Reactive Oxygen Disrupts Mitochondria in MA-10 Tumor Leydig cells and Inhibits Steroidogenic Acute Regulatory (StAR) Protein and Steroidogenesis” Endocrinology 144:2882-91 (2003)
Slevage, D. Hales, D.B ., Rivier, C. “Comparison between the influence of systemic and central injection of alcohol on Leydig cell activity.” Submitted to Alcoholism: Clinical and Experimental Research 28(3): 480-8 (2004)
Allen, J.A., Diemer, T., Janus, P, Held Hales, K., Hales, D.B. “Bacterial Endotoxin Lipopolysaccharide and Reactive Oxygen Species Inhibit Leydig Cell Steroidogenesis via Perturbation of Mitochondria” Endocrine, 25: 265-276 (2004)
Hales, D.B ., Allen, J.A., Shankara, T.C., Janus, P., Buck, S., Diemer, T., Held Hales, K. “Mitochondrial Function In Leydig Cell Steroidogenesis” New York Academy of Sciences 1061:120-134 (2005)
Allen, J.A., Shankara, T.C., Janus, P., Buck, S., Diemer, T., Held Hales, K. Hales, D.B “The mitochondrial membrane potential ( D Y m ), hydrogen ion gradient (?pH) and ATP synthesis are required for Leydig cell steroidogenesis” Endocrinology 147 3924-3935 (2006)
Stammer, K., Edassery, S.L., Barua, A., Bitterman, P., Bahr, J.M., Hales, D.B., Luborsky, J. “Selenium-Binding Protein 1 expression in ovaries and ovarian tumors of the laying hen, a spontaneous model of human ovarian cancer.” Gynecologic Oncology 109(1):115-21 (2008)
Hales, D.B, Zhuge, Y., Lagman, JA, Ansenberger, K, Mahon, C, Barua, A., Luborsky, J., Bahr, JM. “Cyclooxygenase Expression and Distribution in the Normal Ovary and Their Role in Ovarian Cancer in Gallus Domesticus” Endocrine 33:235-24(4 2008)
Barua, A., Edassary, S.L., Bitterman, P., Abramowicz, J.S., Dirks, A., Bahr, J.M., Hales, D.B., Bradaric, M.J., Luborsky, J.L. “Prevalence of anti-tumor antibodies in laying hen model of human ovarian cancer” Int J Gyn Cancer 19(4):500-507 (2009)
Barua A, Bitterman P, Abramowicz J, Bradaric MJ, Edassery SL, Dirks A, Hales DB, Bahr JM and Luborsky JL, (2008) Histopathology of ovarian tumors in laying hens, a preclinical model of human ovarian cancer. International Journal of Gynecological Cancer: 19(4):531-539 (2009)
Zhuge, Y., Ansenberger, K., Mahon, C., Lagman, JA. J., Bahr, J., Hales, D.B. “Cyp1B1 Expression in Ovarian Cancer in the Laying Hen Gallus Dometicus.” Gynecological Oncology 112 (1):171-178 (2009)
Barua A, Abramowicz JS, Bitterman P, Bahr JM, Hales DB, Luborsky JL. OP17.08: Transvaginal ultrasound predicts ovarian tumor associated neo-angiogenesis. Ultrasound Obstet Gynecol; 32:370 (2008)
Ansenberger, K., Zhuge, Y., Lagman, J.A., Richards, C., Barua, A., Bahr, J.M., Hales, D.B., “E-cadherin Expression in Ovarian Cancer in the Laying Hen, Gallus Domesticus, compared to Human Ovarian Cancer” Gynecologic Oncology 113: 362-369(2009)
Barua, A., Bitterman,P., Bahr, J.M., Bradaric, M., Hales, D.B. Luborsky, J., Abramowicz, J. "Detection of tumor associated neo-angiogenesis by Doppler ultrasound during early stage ovarian cancer in laying hens: A preclinical model of human spontaneous ovarian cancer" American Journal of Ultrasound in Medicine (JUM) 29:173–182 (2010)
Ansenberger, K., Richards, C., Barua, A., Bahr, J.M., Luborsky, J.L., Hales, D.B. “Decreased severity of ovarian cancer and increased survival in hens fed a flaxseed enriched diet for one year” Gynecological Oncology 117:341-347 (2010)
Recent key publications with collaborators
Wang, Z.J., Ito, M., Jeffs, B., Hales, D.B., Yu, R.N., Jameson, J.L. “Aromatase Expression is Up-regulated by Targeted Disruption of Dax-1” PNAS USA 98(14):7988-7993 (2001).
Artemenko, I.P., Zhao, D., Hales, D.B., Held Hales, K., Jefcoate, C.R. “Mitochondrial processing of newly synthesized StAR mediates cholesterol transfer to P450scc in adrenal cells.” J Biol Chem 276:46583-46596 (2001)
Moons, D., Jirawatnotai, S., Tsutsui, T., Hales, D.B ., Gibori, G., Fazleabas, AT, Kiyokawa, H. “Luteal differentiation is uncoupled with ovulation in mice deficient for cyclin-dependent kinase-4 (CDK4)” Endocrinology 143:647-654 (2002)
Sorianello, E., Fritz, S., Beyer, C., Hales, D.B ., Mayerhofer, A., Libertun, C., Lux-Lantos, V. “Development Of An Experimental Ovarian Tumor: Immunocytochemical Analysis” Eur J Endocrinol 147:387-395 (2002)
Salvador, L.M., Maizels, E., Miyamoto, E., Yamamoto, H., Hales, D.B., Hunzicker-Dunn, M. “Luteinizing Hormone (LH)-Induced Phosphorylation of p42/44 Mitogen-Activated Protein Kinase (p42/44 MAPK) is Dependent on Protein Kinase A (PKA).” Endocrinology 143: 2986-2994 (2002).
Jirawatnotai, S., Moons. D.S., Stocco, C.S., Franks, R., Hales, D.B. , Gibori, G., Kiyokawa, H. “The CDK Inhibitors p27Kip1 and p21Cip1 Cooperate to Restrict Proliferative Life Span in Differentiating Ovarian Cells” Journal of Biological Chemistry 278:17021-7 (2003)
Granot, Z., Silverman, E., Friedlander, R., Melamed-Book, N., Eimerl, S., Timberg, R., Held Hales, K., Hales, D.B. , Stocco, D.M., Orly , J. “Proteolysis of normal and mutated steroidogenic acute regulatory (StAR) proteins in the mitochondria: the fate of unwanted proteins.” Molecular Endocrinology 17: 2461-2476 (2003)
LeHoux, J. G., A. Fleury, Hales, D.B .. "Phosphorylation of the hamster adrenal steroidogenic acute regulatory protein as analyzed by two-dimensional polyacrylamide gel electrophoreses." Molecular Cellular Endocrinology 215(1-2): 127-34 (2004)
Hauet, T., Yao, Z-X., Bose, H.S., Wall, C.T., Han, Z., Li,W., Hales, D.B ., Miller, W.L., Culty, M., Papadopoulos, V. “Peripheral-Type Benzodiazepine Receptor-Mediated Action of Steroidogenic Acute Regulatory Protein on Cholesterol Entry Into Leydig Cell Mitochondria” Molecular Endocrinology 19(2):540-554 (2005)
Attar, E., Tokunaga, H., Imir, G., Yilmaz, M.B., Redwine, D.,Putman, M., Gurates, B., Attar, R., Yaegashi, N., Hales, D.B., Bulun, S.E. “Prostaglandin E2 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis” Journal of Clinical Endocrinology and Metabolism. 94(2): 623-31 (2009)
Locke, J., Fazli, L., Adomat, H., Smyl, J., Weins, K., Barr, S., Lubik, A., Hales, D.B., Nelson, C., Gleave, M., Guns, E. “A novel communication role for CYP17A1 in the progression of castration-resistant prostate cancer” The Prostate 69(9): 928-37 (2009)
Chapters, Invited Reviews, Editorials
Hales D.B. , Diemer T., Held Hales K. "Review: The Role of Cytokines in Testicular Function" Endocrine 10 :201-217 (1999)
Hales, D.B . “Testicular macrophage modulation of Leydig cell steroidogenesis” Journal of Reproductive Immunology 57:3-18 (2002)
Payne, A.H., Hales, D.B . “ Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones” Endocrine Reviews 25:947-970 (2004).
Payne, A.H., Anakwe, O.O., Hales, D.B., Georgiou, M., Perkins, L.M., and Quinn, P.G. "Regulation of Mitochondrial and Microsomal Cytochrome P-450 enzymes in Leydig cells." In Regulation of Ovarian and Testicular Function (Mahesh, V.B., Dhindsa, D.S., Anderson , E., Kalra, S.P., eds.) Plenum Press, N.Y., pp. 467-487, 1987.
Hales, D.B. “Macrophage-Leydig Cell Interactions: An Overview” in The Leydig Cell (Payne, A.H., Hardy, M.P., Russell, L.D. eds.). Cache River Press, Vienna , IL , pp. 451-466, 1996
Hales, D.B . "Cytokines and Testicular Function" in Cytokines and Reproduction (Hill, J.A. ed.) John Wiley & Sons, NY , NY . pp. 17-42, 2000.
Hedger, M.P., Hales, D.B “Reproductive Immunology of the Male” in Physiology of Reproduction (Neil, J. ed ) Elsevier, San Diego (3 rd edition) Chapter 25, pp:1195-1286, 2006.
Hales, D.B. “Editorial: Gonadal-Specific Transcription Factors—GATA (Go) 4 It!” Endocrinology 124:974-976 (2001)
Hales, D.B. “Editorial: Another piece in the maddening puzzle of declining steroidogenesis in aging Leydig cells.” Journal of Andrology, 23:327-329 (2002)