Article thumbnail

Zeranol Down-Regulates p53 Expression in Primary Cultured Human Breast Cancer Epithelial Cells through Epigenetic Modification

By Weiping Ye, Pingping Xu, Robert Jen, Eric Feng, Saiyi Zhong, Hong Li, Shu-Hong Lin, Jie-Yu Liu and Young C. Lin

Abstract

Epidemiological studies have suggested that there are many risk factors associated with breast cancer. Silencing tumor suppressor genes through epigenetic alterations play critical roles in breast cancer initiation, promotion and progression. As a growth promoter, Zeranol (Z) has been approved by the FDA and is widely used to enhance the growth of beef cattle in the United States. However, the safety of Z use as a growth promoter is still under debate. In order to provide more evidence to clarify this critical health issue, the current study investigated the effect of Z on the proliferation of primary cultured human normal and cancerous breast epithelial cells (PCHNBECs and PCHBCECs, respectively) isolated from the same patient using MTS assay, RT-PCR and Western blot analysis. We also conducted an investigation regarding the mechanisms that might be involved. Our results show that Z is more potent to stimulate PCHBCEC growth than PCHNBEC growth. The stimulatory effects of Z on PCHBCECs and PCHBCECs may be mediated by its down-regulating expression of the tumor suppressor gene p53 at the mRNA and protein levels. Further investigation showed that the expression of DNA methylatransferase 1 mRNA and protein levels is up-regulated by treatment with Z in PCHBCECs as compared to PCHNBECs, which suggests a role of Z in epigenetic modification involved in the regulation of p53 gene expression in PCHBCECs. Our experimental results imply the potentially adverse health effect of Z in breast cancer development. Further study is continuing in our laboratory

Topics: Article
Publisher: Molecular Diversity Preservation International (MDPI)
OAI identifier: oai:pubmedcentral.nih.gov:3111616
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2009). A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation. Cancer Res.
  2. (2000). A prospective trial of midwest breast cancer patients: A p53 gene mutation is the most important predictor of adverse outcome.
  3. (1992). A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell
  4. (1998). Alterations in DNA methylation: A fundamental aspect of neoplasia. Adv. Cancer Res.
  5. (2006). Biphasic effects of zeranol on the growth of estrogen receptor-positive human breast carcinoma cells.
  6. (2007). Characterization of the estrogenic activities of zearalenone and zeranol in vivo and in
  7. (2000). Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues.
  8. (1999). Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour
  9. (1992). CpG islands in mammalian gene promoters are inherently resistant to de novo methylation.
  10. (1998). CpG methylation, chromatin structure and gene silencing-a three-way connection.
  11. (2006). Differential requirement for DNA methyltransferase 1 in maintaining human cancer cell gene promoter hypermethylation. Cancer Res.
  12. (2000). DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet.
  13. (1980). DNA methylation and gene function. Science
  14. (2001). DNA methylation in ovarian cancer. II. Expression of DNA methyltransferases in ovarian cancer cell lines and normal ovarian epithelial cells.
  15. (2003). DNA methylation in serum of breast cancer patients: An independent prognostic marker. Cancer Res.
  16. (2006). DNA methylation-dependent epigenetic regulation of gene expression in MCF-7 breast cancer cells. Epigenetics
  17. (2002). Estrogenic down-regulation of protein tyrosine phosphatase gamma (PTP gamma) in human breast is associated with estrogen receptor alpha. Anticancer Res.
  18. (2003). Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Clin. Cancer Res.
  19. (1995). Expression of antsense to DNA methyltransferase mRNA induces DNA demethylation and inhibits tumorigenesis.
  20. (2009). FAK overexpression and p53 mutations are highly correlated in human breast cancer.
  21. (2010). Function and regulatory mechanisms of the candidate tumor suppressor receptor protein tyrosine phosphatase gamma (PTPRG) in breast cancer cells. Anticancer Res.
  22. (2009). Gene-set analysis and reduction. Briefings Bioinf.
  23. (2008). High growth rate of girls with precocious puberty exposed to estrogenic mycotoxins.
  24. (1998). Imprinting and the initiation of gene silencing in the germ line. Cell
  25. In vitro transformation of MCF-10A cells by sera harvested from heifers two months post-Zeranol implantation.
  26. (2006). Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer. Carcinogenesis
  27. (1993). Increased cytosine DNA-methyltransferase activity during colon cancer progression.
  28. (2010). Intratumoral estrogen disposition in breast cancer. Clin. Cancer Res.
  29. (2005). Investigations on cellular proliferation induced by zearalenone and its derivatives in relation to the estrogenic parameters.
  30. (2002). Involvement of breast epithelial-stromal interactions in the regulation of protein tyrosine phosphatase-γ (PTP γ) mRNA expression by estrogenically active agents. Breast Cancer Res.
  31. (2001). Methylation in the p53 promoter is a supplementary route to breast carcinogenesis: correlation between CpG methylation in the p53 promoter and the mutation of the p53 gene in the progression from ductal carcinoma in situ to invasive ductal carcinoma.
  32. (2004). Methylation profile of the promoter CpG islands of 31 genes that may contribute to colorectal carcinogenesis. World
  33. (1999). Methylation profiling of CpG islands in human breast cancer cells.
  34. (2009). Mitogenic activity of zeranol in human breast cancer cells is enhanced by leptin and suppressed by gossypol. Anticancer Res.
  35. (2004). Multistage carcinogenesis.
  36. Mutations in the p53 tumor suppressor gene and early onset breast cancer.
  37. (2002). Normal breast epithelial cells induce p53-dependent apoptosis and p53-independent cell cycle arrest of breast cancer cells. Breast Cancer Res.
  38. (1989). Occupational exposure to zeranol, an animal growth promoter.
  39. (1999). p53 and cancer therapy: a double-edged sword.
  40. (2008). Presence of dominant negative mutation of TP53 is a risk of early recurrence in oral cancer. Cancer Lett.
  41. (2008). Red meat consumption during adolescence among premenopausal women and risk of breast cancer. Cancer Epidemiol. Biomarkers Prev.
  42. (2007). Retinoblastoma pathway dysregulation causes DNA methyltransferase 1 overexpression in cancer via MAD2-mediated inhibition of the anaphase-promoting complex.
  43. (2007). Semen quality of fertile US males in relation to their mothers’ beef consumption during pregnancy.
  44. Serum harvested from heifers one month post-zeranol implantation stimulates MCF-7 breast cancer growth.
  45. (1995). Suppression of intestinal neoplasia by DNA hypomethylation. Cell
  46. (2000). Surfing the p53 network. Nature
  47. (1992). Tamoxifen prevents induction of hepatic neoplasia by zeranol, an estrogenic food contaminant.
  48. (1999). The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res.
  49. (1997). The molecular epidemiology of p53 gene mutations in human breast cancer. Trends Genet.
  50. (2004). Transformation of MCF-10A human breast epithelial cells by zeranol and estradiol-17beta. Breast J.
  51. (2009). Zeranol enhances the proliferation of pre-adipocytes in beef heifers. Anticancer Res.