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The Interaction of Leptin, Zeranol and Gossypol in Breast Cancer

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The Interaction of Leptin, Zeranol and Gossypol in Breast Cancer The interaction of leptin, zeranol and gossypol in breast cancer development Thesis Presented in Partial Fulfillment of the Requirements for the Degree of Master in Science in the Graduate School of The Ohio State University By Pingping Xu, M.S Graduate Program in Veterinary Bioscience The Ohio State University 2010 Thesis Committee: Dr. Young C. Lin, Advisor Dr. Huey-Jen Lee Lin Dr. Robert J.Lee Copyright by Pingping Xu 2010 Abstract Both breast cancer and obesity are very serious problems in the U.S. Leptin, mainly secreted by adipocytes, is a product of the obese (ob) gene and plays an important role in breast cancer development. Leptin expression is up-regulated in obesity and it can promote breast cancer cell growth. On the other hand, exposure to environmental estrogens has been found to be directly related to breast cancer. Zeranol (Z), is a non- steroidal anabolic growth promoter with estrogenic activity and widely used in the U.S beef industry. Another natural compound extracted from cottonseed and used as an anticancer chemopreventive agent, gossypol, can inhibit breast cancer growth. It is suggested gossypol could be used as potential chemopreventive food components. The current study demonstrated that Z stimulated the proliferation of primary cultured human normal and cancerous breast epithelial cells and sera collected from Z-implanted beef heifers stimulated the growth of pre-adipocytes isolated from breast cancer patients. This study is focusing on evaluation of Z and bio-active Z-containing sera collected from Z-implanted beef and its adverse health risk to human consumption of Z-containing meat produced from Z-implanted beef cattle. We hypothesize that Z might increase the risk of breast cancer in obese women. Cell proliferation assay, ELISA analysis, RT-PCR and Western blotting were conducted. The primary cultured human normal breast epithelial cells (HNBECs) and pre-adipocytes (HNBPADs) were isolated from human normal breast tissues and cultured, the primary cultured human breast cancer epithelial cells (HBCECs) were isolated from breast cancer ii patients and cultured. The MTT assay to evaluate the proliferation of HNBECs, HBCECs, and HNBPADs was carried out. The sera used in the MTT assay were: non-zeranol serum (NZS) dropped from the non-zeranol-implantation beef heifers at day 0 (NZS-D0) and at day 30 post zeranol-implantation (NZS-D30); zeranol-serum (ZS) harvested from zeranol implantation heifers at day 0 (ZS-D0) and day 30 post zeranol-implantation (ZS- D30). The concentration for both NZS and ZS was 0.2, 1.0 and 5.0% in cultured medium. Our result shows both Z and lp can increase primary cultured HNBECs, HNCECs, PADs and MCF-7 Adr cell growth. ZS have a greater power to stimulate HNBECs and HNBPADs growth than NZS and the combination of Z with leptin increase HNBECs and HNBPADs cyclin D1 mRNA expression and down-regulate P53 or PTPg mRNA expression while (-)-gossypol revert its effect in MCF-7 Adr cells, primary cultured PADs, HBCECs and HBNECs. Leptin can increase the breast cancer cells’ sensitivity to Z and Z increase the ObR mRNA expression both in primary cultured HBCECs and MCF-7 Adr cells. Z stimulates primary cultured HNBECs and PADs secrete leptin. These results pointed out that the leptin may be involved in enhancing the HNBPADs sensitivity to ZS and there is interaction between Z and leptin in HNBPADs. It suggests Z maybe more harmful to obese patients and might play a role in breast cancer development and (-)-gossypol may serve as a potential chemopreventive agent and play an important role in breast cancer chemoprevention. iii Dedication Dedicated to my parents, my husband, my son and my daughter iv Acknowledgments I would like to express my appreciation to my advisor Dr. Young C. Lin for his guidance, patience, insight and support throughout the course of this research during the past three years. I also acknowledge the efforts and contribution of my committee members, Dr. Huey-Jen Lee Lin and Dr. Robert J. Lee, who provide me advice and direction during the course of my project. A special note of thanks is extended to all the members in Dr. Lin’s laboratory for their friendly help in this project. My sincere gratitude to my parents, my husband, my son and my daughter for continued support and enjoy the life with me. v Vita April 18, 1965…………..born in Guanyun County, Jiangshu Province, P.R.China 1982--1987 …………….Bachelor of Medicine, Zhejiang University, P.R.China 1987—1996 ……. ……..Worked in Quzhou Municipal Sanitary and Anti-epidemic Station, P.R.China. 1996---2010 ……………Worked as an instructor in Jinhua College of Profession and Technology, P. R. China. 2004--2005 …………….Graduate student in the Department of Human Nutrition in OSU 2007--2010 …………….Graduate student in the Department of Veterinary Bioscience in OSU Publications Pingping Xu, Weiping Ye, Robert Jen, Shu-Hong Lin, Chieh-Ti Kuo, Young C. Lin Mitogenic activity of Zeranol in human breast cancer cells is enhanced by leptin and suppressed by gossypol Anticancer Res 29(11): 4621-4628, 2009 Weiping Ye, Pingping Xu, Walter R. Threlfall, Robert Jen, Hong Li, Shu-Hong Lin, Cheik-Ti Kuo, Young C. Lin Zeranol Enhances the Proliferation of Pre-adipocytes in Beef Heifers Anticancer Res 29(12): 5045-5052, 2009 Pingping Xu, Weiping Ye, Hong Li, Shu-Hong Lin, Chieh-Ti Kuo, Young C. Lin Zeranol (Z)-containing beef serum stimulates proliferation of human normal breast epithelial cells (HNBECs), AACR annual meeting, Denver, CO Apr. 22, 2009 vi Pingping Xu, Weiping Ye, Chieh-Ti Kuo, Young C. Lin (-)-Gossypol inhibits zeranol and leptin-induced MCF-7 adr cell proliferation AACR annual meeting, San Diego, CA. Apr. 13, 2008 Pingping Xu, Weiping Ye, Qiakuang Yuan Measurement of Particular Size in Aerosol Atomized by Different Media. China Public Health 17(3):265, 2001 Weiping Ye, Qiakuang Yuan, Pingping Xu Study on A Compound Disinfectant of Glutaraldehyde Chinese Journal of Disinfection. 16(4):209-12,1999 Pingping Xu. Evaluation of the Albendazole’s Effectiveness to Verminosis Zhejiang Preventive Medicine and Disease Surveillance 6:74, 1994 Pingping Xu Investigating the Rate of Students’ Tooth Brushing in Quzhou Elementary School. Zhejiang Preventive Medicine and Disease Surveillance 5:16, 1993 Field of Study Major Field: Veterinary Biosciences Study in breast cancer and obesity vii Table of Contents Page Abstract ……………………………………………………………………………...…ii Dedication……………………………………………………………………………...iv Acknowledgements…………………………………………………………….….…...v Vita…………………………………………………………………………….………vi List of Figures………………………………………………………………………….x Abbreviations..………………………………………………………………………..xiii CHAPTERS 1. Introduction……………………………………………………….…………….1 2. The Interaction of Leptin, Zeranol and Gossypol in Human Normal and Cancer Breast Epithelial Cells Abstract………………………………………………………….….……..…….6 Introduction………………………………………………………………….…..8 Materials and Methods…………………………………………………………10 Results…………………………………………………………………….……21 Discussions………………………………………………….............................24 3. The Interaction of Leptin, Zeranol and Gossypol in Human Normal Breast Pre- adipocyte Growth Abstract……………………………………………………………..………….53 Introduction……………………………………………………………….……55 viii Materials and Methods…………………………………………………….….57 Results……………………………………………………………………..….63 Discussions………………………………………………………………..….65 4. Conclusion remarks…………………………………………….…………….79 Literature cited…………………………………………….…..….……..………..82 .. ix List of Figures Figure Page Figure 2.1 The effect of leptin on MCF-7 Adr cell growth………………………..…..30 Figure 2.2 Effect of leptin on primary cultured HBCECs growth…………………..…31 Figure 2.3 Comparison of effective dose of leptin on primary cultured HBCECs and HBNECs growth……………………………………………..……….…..…32 Figure 2.4 The effect of Zeranol on MCF-7 Adr cell growth………………………..…33 Figure 2.5 Effect of zeranol on primary cultured HBCECs growth……………………34 Figure 2.6 Comparison of MCF-7 Adr cell growth with pre-lp and post-lp treatment...35 Figure 2.7 Comparison of the primary cultured HBCECs growth with pre-lp and post-lp treatment……..……….………………………………………...…36 Figure 2.8 Comparison of the proliferative effect of leptin, zeranol, pre-lp and post-lp treatment in MCF-7 Adr cells…………………………….….……37 Figure 2.9 Comparison of the proliferative effect of leptin, zeranol, pre-lp and post-lp treatment in MCF-7 Adr cells………………………………..……38 Figure 2.10 Effects of leptin (lp), zeranol (Z) and (-)-gossypol (G) on MCF-7 Adr cell proliferation……………………………………...…………………...39 Figure 2.11 Effects of leptin and (-)-gossypol (G) on primary cultured HBNECs growth………………………………………………………………………40 Figure 2.12 Effects of none-zeranol serum on ECs isolated from non-leptin cultured x tissues………………..…….………………………………………………41 Figure 2.13 Effects of non-zeranol serum on ECs from1.5 nM of leptin cultured tissues…………………...………………………………………………….42 Figure 2.14 Effects of zeranol serum on ECs from non-leptin cultured tissues……….43 Figure 2.15 Effects of zeranol serum on ECs from 1.5 nM of leptin cultured tissues...44 Figure 2.16 Effects of leptin and zeranol and (-)-gossypol alone or combination on cyclin D1 expression in MCF-7 Adr cells…….………………………….45 Figure 2.17 Effects of leptin and zeranol on cyclin D1 expression in HBCECs….…..46 Figure 2.18 Effects of leptin, zeranol and (-)-gossypol on cyclin D1 expression in HBNECs………………………………..…………………………….….47 Figure 2.19 Zeranol up-regulated Cyclin D1 protein expression in HBNECs……..….48 Figure 2.10 Effects of leptin, zeranol and (-)-gossypol alone or combination on P53 expression in MCF-7/Adr cells…………………………………...49
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