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Grant Details

Grant Number: 5R21CA094718-03 Interpret this number
Primary Investigator: Lin, Young
Organization: Ohio State University
Project Title: Exposure to Beef Growth Promoter in Breast Cancer
Fiscal Year: 2003


Abstract

DESCRIPTION (provided by applicant): Zeranol (Z) is a nonsteroidal agent with estrogenic activity that is used as a growth promoter in the U.S. beef and veal industries. Thus, people are exposed to Z via dietary intake as a consequence of the direct and intentional introduction of the compound into food animals by veterinary professionals on behalf of beef industry farmers. Our contention is that the consumption of food products, particularly beef, derived from food animals treated with Z has a potential health impact on human consumers, particularly with respect hormone-sensitive organs. This concern arises from our own experimental data using in vitro models derived from human breast cells and tissues which demonstrates the presence of heat-stable biological and estrogenic activity in extracts of meat derived from Z-treated cattle. These experimental data provide a putative link between the long-term dietary exposure to low-levels of Z and potential risk of breast cancer. The proposed study is designed to assess the relationship between exposure to Z via beef consumption and breast cancer in human subjects. Normal subjects and breast cancer patients will be categorized according to level of beef consumption. Levels of Z in breast, serum and urine and expression levels of mechanism-based molecular biomarkers in breast tissues will be determined as indicators of exposure and risk for breast cancer. Measurement of Z levels in purchased beef products from across the U.S., and confirmation of biological activity (mitogenic activity; altered expression of mechanism-based molecular biomarkers) in human and beef samples is aimed to solidify the association among beef consumption, Z exposure and breast cancer risk. The Specific Aims of the study are: (1) To develop an ELISA designed for the routine measurement of Z in commercial meats and human tissues and fluids; (2) To investigate relationships among beef consumption, levels of Z in breast, serum and urine, and breast cancer in patients of The Ohio State University Hospital; (3) To measure Z levels in commercially available beef products purchased in supermarkets from 5 different regions across the U.S.; and (4) To utilize established in vitro model systems to confirm the presence of biological activity (mitogenic activity; altered expression of mechanism-based molecular biomarkers) in specimens from human subjects and commercial beef products in which Z levels were detected. The proposed study utilizes our diverse multi disciplinary expertise in reproductive endocrinology, clinical and surgical oncology, breast cancer, veterinary medicine and medicinal chemistry to explore our contention that beef consumption may pose a human health risk. The proposed study will link beef production practices, beef consumption and human breast cancer in an integrated and comprehensive approach that will clarify the potential role of Z exposure in breast cancer, identify potentially valuable mechanism-based molecular biomarkers that could lead to new tools for exposure assessment in breast cancer, provide a fertile basis for future research directions in this important area, and provide information that may be useful to federal regulatory agencies in making informed decisions regarding the status of current regulations and practices in the use of growth promoters in beef destined for human consumption.



Publications

Function and regulatory mechanisms of the candidate tumor suppressor receptor protein tyrosine phosphatase gamma (PTPRG) in breast cancer cells.
Authors: Shu S.T. , Sugimoto Y. , Liu S. , Chang H.L. , Ye W. , Wang L.S. , Huang Y.W. , Yan P. , Lin Y.C. .
Source: Anticancer research, 2010 Jun; 30(6), p. 1937-46.
PMID: 20651337
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Keratinocyte growth factor (KGF) regulates estrogen receptor-alpha (ER-alpha) expression and cell apoptosis via phosphatidylinositol 3-kinase (PI3K)/Akt pathway in human breast cancer cells.
Authors: Chang H.L. , Sugimoto Y. , Liu S. , Wang L.S. , Huang Y.W. , Ye W. , Lin Y.C. .
Source: Anticancer research, 2009 Aug; 29(8), p. 3195-205.
PMID: 19661335
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(-)-Gossypol reduces invasiveness in metastatic prostate cancer cells.
Authors: Huang Y.W. , Wang L.S. , Dowd M.K. , Wan P.J. , Lin Y.C. .
Source: Anticancer research, 2009 Jun; 29(6), p. 2179-88.
PMID: 19528479
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Conjugated linoleic acid induces apoptosis through estrogen receptor alpha in human breast tissue.
Authors: Wang L.S. , Huang Y.W. , Liu S. , Yan P. , Lin Y.C. .
Source: BMC cancer, 2008-07-24; 8, p. 208.
EPub date: 2008-07-24.
PMID: 18652667
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Primary cultured human breast epithelial cells up-regulate protein disulfide isomerase in response to zeranol.
Authors: Updike M.S. , Sawdy J.C. , Wang L.S. , Liu S. , Huang Y.W. , Ye W. , Farrar W.B. , Lin Y.C. , Wick M. .
Source: Anticancer research, 2007 Jan-Feb; 27(1A), p. 407-10.
PMID: 17352260
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Modulation of multidrug resistance gene expression in human breast cancer cells by (-)-gossypol-enriched cottonseed oil.
Authors: Ye W. , Chang H.L. , Wang L.S. , Huang Y.W. , Shu S. , Dowd M.K. , Wan P.J. , Sugimoto Y. , Lin Y.C. .
Source: Anticancer research, 2007 Jan-Feb; 27(1A), p. 107-16.
PMID: 17352222
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Effects of serum on (-)-gossypol-suppressed growth in human prostate cancer cells.
Authors: Huang Y.W. , Wang L.S. , Chang H.L. , Ye W. , Sugimoto Y. , Dowd M.K. , Wan P.J. , Lin Y.C. .
Source: Anticancer research, 2006 Sep-Oct; 26(5A), p. 3613-20.
PMID: 17094491
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Effect of keratinocyte growth factor on cell viability in primary cultured human prostate cancer stromal cells.
Authors: Huang Y.W. , Wang L.S. , Chang H.L. , Ye W. , Shu S. , Sugimoto Y. , Lin Y.C. .
Source: The Journal of steroid biochemistry and molecular biology, 2006 Jul; 100(1-3), p. 24-33.
EPub date: 2006-07-18.
PMID: 16854582
Related Citations

Molecular mechanisms of (-)-gossypol-induced apoptosis in human prostate cancer cells.
Authors: Huang Y.W. , Wang L.S. , Chang H.L. , Ye W. , Dowd M.K. , Wan P.J. , Lin Y.C. .
Source: Anticancer research, 2006 May-Jun; 26(3A), p. 1925-33.
PMID: 16827126
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Keratinocyte growth factor (KGF) induces tamoxifen (Tam) resistance in human breast cancer MCF-7 cells.
Authors: Chang H.L. , Sugimoto Y. , Liu S. , Ye W. , Wang L.S. , Huang Y.W. , Lin Y.C. .
Source: Anticancer research, 2006 May-Jun; 26(3A), p. 1773-84.
PMID: 16827106
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Conjugated linoleic acid (CLA) modulates prostaglandin E2 (PGE2) signaling in canine mammary cells.
Authors: Wang L.S. , Huang Y.W. , Liu S. , Chang H.L. , Ye W. , Shu S. , Sugimoto Y. , Funk J.A. , Smeaks D.D. , Hill L.N. , et al. .
Source: Anticancer research, 2006 Mar-Apr; 26(2A), p. 889-98.
PMID: 16619484
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Conjugated linoleic acid (CLA) up-regulates the estrogen-regulated cancer suppressor gene, protein tyrosine phosphatase gamma (PTPgama), in human breast cells.
Authors: Wang L.S. , Huang Y.W. , Sugimoto Y. , Liu S. , Chang H.L. , Ye W. , Shu S. , Lin Y.C. .
Source: Anticancer research, 2006 Jan-Feb; 26(1A), p. 27-34.
PMID: 16475675
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Effects of human breast stromal cells on conjugated linoleic acid (CLA) modulated vascular endothelial growth factor-A (VEGF-A) expression in MCF-7 cells.
Authors: Wang L.S. , Huang Y.W. , Sugimoto Y. , Liu S. , Chang H.L. , Ye W. , Shu S. , Lin Y.C. .
Source: Anticancer research, 2005 Nov-Dec; 25(6B), p. 4061-8.
PMID: 16312046
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Decreased MCF-7 breast cancer cell proliferation by serum from a selected line of beef cattle.
Authors: Updike M.S. , Davis M.E. , Wang L.S. , Huang Y.W. , Wick M. , Lin Y.C. .
Source: Anticancer research, 2005 Mar-Apr; 25(2A), p. 871-4.
PMID: 15868921
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Transformation of MCF-10A human breast epithelial cells by zeranol and estradiol-17beta.
Authors: Liu S. , Lin Y.C. .
Source: The breast journal, 2004 Nov-Dec; 10(6), p. 514-21.
PMID: 15569208
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Function analysis of estrogenically regulated protein tyrosine phosphatase gamma (PTPgamma) in human breast cancer cell line MCF-7.
Authors: Liu S. , Sugimoto Y. , Sorio C. , Tecchio C. , Lin Y.C. .
Source: Oncogene, 2004-02-12; 23(6), p. 1256-62.
PMID: 14676845
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Estrogenic down-regulation of protein tyrosine phosphatase gamma (PTP gamma) in human breast is associated with estrogen receptor alpha.
Authors: Liu S. , Sugimoto Y. , Kulp S.K. , Jiang J. , Chang H.L. , Park K.Y. , Kashida Y. , Lin Y.C. .
Source: Anticancer research, 2002 Nov-Dec; 22(6C), p. 3917-23.
PMID: 12553013
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