Inflammation and oxidative stress contribute to numerous pathologies including cancer and decreased reproductive health. Our studies examine the mechanisms through which immune-endocrine interactions contribute to hormonal carcinogenesis and control steroid hormone biosynthesis, metabolism and action.
Ovarian cancer is the leading cause of death from gynecological malignancies due to the late stage at which it is usual detected. With the exception of the laying hen no other animals are inflicted with spontaneous ovarian surface epithelial 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 in etiology of ovarian cancer. Our studies involve dietary intervention strategies and examine basic mechanisms of cancer pathogenesis.
Our recent studies have shown that feeding cancer prone hens a diet enriched with 10% flaxseed for one year caused a significant reduction in the severity of cancer in hens which were afflicted. This result not only holds promise for therapeutic applications of flaxseed or its biologically active constituents --omega-3 fatty acids in the seed germ or the phytoestrogen antioxidants in the hull, but also gives us new insight into the pathobiology of ovarian cancer. We have shown that the flax diet causes a significant reduction in inflammatory prostaglandin (PGE2), suggesting that the progression of ovarian cancer is driven by inflammation. The initial long term feeding study, which employed hens that had completed their second year of lay, caused significant reduction in severity of the disease, and an improvement of overall wellbeing of the chickens, but did not reduce the incidence of spontaneous epithelial ovarian cancer in the hens. Reasoning that the cumulative damage of 400 ovulations had already created the pro-carcinogenic microenvironment in the ovarian surface epithelium --in fact, many of the birds which were recruited to the study likely were already harboring occult disease --thus prevention was not possible, but amelioration of the disease was the achievable with the intervention. Based on this logic we conducted a 5 yearlong study feeding hens flaxseed from the time of their first lay, when they were about 6 months old. At 6 month intervals for 4 years 20 hens from the control and flax fed groups were analyzed. The hens were cancer free until they reached 2.5 years of age, coincident with the time we had initiated the prior study. At the age when cancer was first evident, was when prostaglandin levels and expression of the cyclooxygenase enzymes began to increase --in parallel to the increase in cancer. Importantly, the flax-fed hens had a significant decrease in cancer incidence, and the flax-fed hens with cancer presented with decreased severity. Our current studies are examining the individual contribution of flax derived omega-3 fatty acids vs. phytoestrogen lignans to the chemo-preventative and chemo-suppressive effects of whole flaxseed. Studies examine alterations in three classes of surrogate endpoints --inflammation (prostaglandin pathways); estrogen metabolism, and signaling, and oxidative stress pathways.
Our studies also examine the mechanisms through which inflammation adversely affects the reproductive capacity via perturbation of gonadal steroid biosynthesis. These studies have revealed that there is a biphasic inhibition of testosterone production: an acute inhibition due to reactive oxygen mediated perturbation of Leydig cell mitochondria, and a prolonged, cytokine-mediated transcriptional repression of steroidogenic enzyme gene expression. Oxidant mediated senescence likely contributes to declining reproductive capacity and performance in the aging male, and understanding the mechanisms through which inflammation and oxidative stress affect testosterone biosynthesis will provide the basis for therapeutic modalities for natural methods of preventing androgenic senescence.
Education & training
Allen, J.A., Diemer, T., Held Hales, K., Janus, P., Hales, D.B. “Bacterial Endotoxin Lipopolysaccharide and Reactive Oxygen Species Inhibit Leydig Cell Steroidogenesis via Perturbation of Mitochondria” Endocrine, 25: 265-276 (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)
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 (m), hydrogen ion gradient (ΔpH) 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)
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)
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)
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)
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)
Palladino MA, Pirlamarla PR, McNamara J, Sottas CM, Korah N, Hardy MP, Hales, D.B. “Normoxic Expression of Hypoxia-Inducible Factor-1 in Rat Leydig Cells In Vivo and In Vitro”. J Androl. 32: 307-323 (2011)
Barua A, Bitterman P, Bahr JM, Basu S, Sheiner E, Bradaric MJ, Hales DB, Luborsky JL, Abramowicz JS. Contrast-enhanced sonography depicts spontaneous ovarian cancer at early stages in a preclinical animal model. Journal of Ultrasound in Medicine.30:333-45 (2011)
Aghazadeh Y, Rone MB, Blonder J, Ye X, Veenstra T, Hales DB, Culty M , Papadopoulos V “Hormone-induced 14-3-3γ adaptor protein regulates steroidogenic acute regulatory protein activity and steroid biosynthesis in MA-10 Leydig cells” J Biological Chemistry 10.1074/jbc.M112.339580 epub 2012/3/20 (2012)
Eilati, E., Pan, L., Bahr, J.M., Hales, D.B. “Age dependent increase in Prostaglandin pathway coincides with onset of ovarian cancer in laying hens” Prostaglandins, Leukotrienes & Essential Fatty Acids 10.1016/j.plefa.2012.09.003 (2012)
Gato, WE, Hales, DB, Means, JC “Hepatic Gene Expression Analysis of 2-Aminoanthracene Exposed Fisher-344 Rats Reveal Patterns Indicative of Liver Carcinoma and Type 2 Diabetes” he Journal of Toxicological Sciences 37(5):1001-1016 (2012)
Machado, SA, Bahr, JM, Hales, DB, Braundmeier, AD, Quade, BJ, Nowak, RA “Validation of the Aging Hen (Gallus gallus domesticus) as an Animal Model for Uterine Leiomyomas” Biology of Reproduction 87 (4):1-11 (2012)
Eilati, E., Bahr, J.M., Hales, D.B. “Long Term Consumption of Flaxseed-Enriched Diet Decreases Ovarian Cancer Incidence and Prostaglandin E2 in Hens.” Gynecologic Oncology 130:620-628 (2013)
Eilati, E, Zhuge, Y, Hales, KH, Ansenberger Fricano, K, Rui, Y, van Breemen, RB, Hales, DB “Flaxseed enriched diet-mediated reduction in ovarian cancer severity is correlated to the reduction of prostaglandin E2 in laying hen ovaries.” Prostaglandins, Leukotrienes & Essential Fatty Acids 89:179-87 (2013)
Eilati, E, Small, CF, McGee, SR, Kurrey, NK, Hales, DB “Anti-inflammatory effects of fish oil in ovaries of laying hens target prostaglandin pathways.” Lipids in Health and Disease 12 (1):152-163 (2013).
Lengyel, E, Burdette, JE, Kenny, HA, Matei, D, Pilrose, J, Haluska, P, Nephew, KP, Hales, DB, Stack, MS “Review: Epithelial ovarian cancer experimental models” Oncogene 33:3619-3633 (2014)
Hales, K.H, Speckman S., Kurrey, N.K., Hales, D.B. “Uncovering Molecular Events Associated with Chemosuppressant Effects of Flaxseed: A Microarray Analysis in Laying Hen Model of Ovarian CancerBMC Genomics (2014), 15 (1):709 doi:10.1186/1471-2164-15-709
Dikshit, A, Adriao-Gomes Filho, M, Eilati, E, McGee, S, Small C, Gao, C, Klug, T, Hales DB, “Flaxseed reduces the pro-carcinogenic microenvironment in the ovaries of normal hens by altering the prostaglandin and estrogen pathways in a dose dependent manner” British Journal of Nutrition (2015) 113:1384-1395
2011-2017 National Center for Complementary and Alternative Medicine NIH 1R01 AT005295-01 (PI Hales) “Flax seed therapy for the prevention of ovarian cancer.” $1,840,000
2014-2017 Team Science Grant, Simmons Cancer Institute at SIU, Co-Pi (Brard, Hales, K Hales) “Flaxseed as maintenance therapy for ovarian cancer patients in remission” $100,000
Endowed lecture at University of Michigan, Anita Payne Lecture “Molecular targets for dietary intervention, new insights into the pathogenesis of ovarian cancer.” Oct 14, 2011, Ann Arbor, MI.
Keynote speaker at University of Colorado Anschutz Medical Center Cancer Center Basic Science Symposium on Inflammation, Oxidative Stress and Cancer, “Molecular targets for dietary intervention, new insights into the pathogenesis of ovarian cancer.” Jan 24, 2012, Denver, CO
Plenary presentation at AACR Advances in Ovarian Cancer Research symposium, “Nutritional intervention for prevention of ovarian cancer in a natural model--the laying hen” Oct 20, 2015, Orlando, FL