Article thumbnail
Location of Repository

Partial Inhibition of Estrogen-Induced Mammary Carcinogenesis in Rats by Tamoxifen: Balance between Oxidant Stress and Estrogen Responsiveness

By Bhupendra Singh, Nimee K. Bhat and Hari K. Bhat

Abstract

Epidemiological and experimental evidences strongly support the role of estrogens in breast tumor development. Both estrogen receptor (ER)-dependent and ER-independent mechanisms are implicated in estrogen-induced breast carcinogenesis. Tamoxifen, a selective estrogen receptor modulator is widely used as chemoprotectant in human breast cancer. It binds to ERs and interferes with normal binding of estrogen to ERs. In the present study, we examined the effect of long-term tamoxifen treatment in the prevention of estrogen-induced breast cancer. Female ACI rats were treated with 17β-estradiol (E2), tamoxifen or with a combination of E2 and tamoxifen for eight months. Tissue levels of oxidative stress markers 8-iso-Prostane F2α (8-isoPGF2α), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) were quantified in the mammary tissues of all the treatment groups and compared with age-matched controls. Levels of tamoxifen metabolizing enzymes cytochrome P450s as well as estrogen responsive genes were also quantified. At necropsy, breast tumors were detected in 44% of rats co-treated with tamoxifen+E2. No tumors were detected in the sham or tamoxifen only treatment groups whereas in the E2 only treatment group, the tumor incidence was 82%. Co-treatment with tamoxifen decreased GPx and catalase levels; did not completely inhibit E2-mediated oxidative DNA damage and estrogen-responsive genes monoamine oxygenase B1 (MaoB1) and cell death inducing DFF45 like effector C (Cidec) but differentially affected the levels of tamoxifen metabolizing enzymes. In summary, our studies suggest that although tamoxifen treatment inhibits estrogen-induced breast tumor development and increases the latency of tumor development, it does not completely abrogate breast tumor development in a rat model of estrogen-induced breast cancer. The inability of tamoxifen to completely inhibit E2-induced breast carcinogenesis may be because of increased estrogen-mediated oxidant burden

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3180376
Provided by: PubMed Central

Suggested articles

Citations

  1. (1994). A comparative study of tamoxifen metabolism in female rat, mouse and human liver microsomes.
  2. (1991). A metabolically competent human cell line expressing five cDNAs encoding procarcinogen-activating enzymes: application to mutagenicity testing.
  3. (1994). alphaHydroxytamoxifen, a metabolite of tamoxifen with exceptionally high DNAbinding activity in rat hepatocytes.
  4. (2003). Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling.
  5. (2005). Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer.
  6. (2009). Antioxidant butylated hydroxyanisole inhibits estrogen-induced breast carcinogenesis in female ACI rats.
  7. (1986). Ari-Ulubelen A
  8. (2005). c-Myc suppresses p21WAF1/CIP1 expression during estrogen signaling and antiestrogen resistance in human breast cancer cells.
  9. (2006). Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention.
  10. (2006). Catechol quinones of estrogens in the initiation of breast, prostate, and other human cancers: keynote lecture.
  11. (1998). CIDE, a novel family of cell death activators with homology to the 45 kDa subunit of the DNA fragmentation factor.
  12. (2004). Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6.
  13. (2002). Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells.
  14. (2003). Critical role of oxidative stress in estrogen-induced carcinogenesis.
  15. (1997). CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver.
  16. (2003). CYP2D6-mediated catalysis of tamoxifen aromatic hydroxylation with an NIH shift: similar hydroxylation mechanism in chicken, rat and human liver microsomes.
  17. (1997). Cytological evaluation of biological prognostic markers from primary breast carcinomas.
  18. (2010). Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats.
  19. (2004). Differential oxidant potential of carcinogenic and weakly carcinogenic estrogens: Involvement of metabolic activation and cytochrome P450.
  20. (1980). Distribution of CuZn superoxide dismutase and Mn superoxide dismutase in human tissues and extracellular fluids. Acta Physiol Scand Suppl 492:
  21. (1994). DNA single-strand breaks in kidneys of Syrian hamsters treated with steroidal estrogens: hormone-induced free radical damage preceding renal malignancy.
  22. (2008). Effects of estrogen on gene expression profiles in mouse hypothalamus and white adipose tissue: target genes include glutathione peroxidase 3 and cell deathinducing DNA fragmentation factor, alpha-subunit-like effector A.
  23. (2000). Endogenous estrogens as carcinogens through metabolic activation.
  24. (2004). Epelboym I
  25. (2008). ERRgamma mediates tamoxifen resistance in novel models of invasive lobular breast cancer.
  26. (2001). Estrogen and the risk of breast cancer.
  27. (1987). Estrogen carcinogenesis in Syrian hamster tissues: role of metabolism.
  28. (2004). Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats.
  29. (2004). Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancer.
  30. (2006). Estrogen-related receptorsstimulated monoamine oxidase B promoter activity is down-regulated by estrogen receptors.
  31. (2008). Estrogeninduced breast cancer: alterations in breast morphology and oxidative stress as a function of estrogen exposure.
  32. (1990). Free radical generation by redox cycling of estrogens.
  33. (1994). Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s.
  34. (1998). Glucose deprivation-induced cytotoxicity and alterations in mitogen-activated protein kinase activation are mediated by oxidative stress in multidrug-resistant human breast carcinoma cells.
  35. (1993). Gynecologic tumors in tamoxifentreated women with breast cancer.
  36. (1999). IARC monographs on the evaluation of carcinogenic risks to humans: hormonal contraception and postmenopausal hormone therapy.
  37. (2000). Identification of hepatic tamoxifen-DNA adducts in mice: alpha-(N(2)-deoxyguanosinyl)tamoxifen and alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide.
  38. (2002). Identification of human CYP forms involved in the activation of tamoxifen and irreversible binding to DNA.
  39. (2001). Importance of complete DNA digestion in minimizing variability of 8-oxo-dG analyses.
  40. (1992). Induction of covalent DNA adducts in rodents by tamoxifen.
  41. (2002). Integration of the non-genomic and genomic actions of estrogen. Membraneinitiated signaling by steroid to transcription and cell biology.
  42. (2001). Intratumoral variations in DNA ploidy and s-phase fraction in human breast cancer.
  43. (1993). Localization of estrogen receptors in interstitial cells of hamster kidney and in estradiolinduced renal tumors as evidence of the mesenchymal origin of this neoplasm.
  44. (2004). Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer.
  45. (2009). Metabolism of histamine in tissues of primary ductal breast cancer.
  46. (1997). Molecular basis of agonism and antagonism in the oestrogen receptor.
  47. (2003). Molecular cloning and characterization of CIDE-3, a novel member of the cell-death-inducing DNAfragmentation-factor (DFF45)-like effector family.
  48. (2001). Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity.
  49. (1997). Ovaryintact, but not ovariectomized female ACI rats treated with 17beta-estradiol rapidly develop mammary carcinoma.
  50. (2006). Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats.
  51. (2005). Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin.
  52. (2007). Pathways to tamoxifen resistance.
  53. (2002). Ploidy differences between hormone- and chemical carcinogen-induced rat mammary neoplasms: comparison to invasive human ductal breast cancer.
  54. (2002). Prevention of solely estrogen-induced mammary tumors in female aci rats by tamoxifen: evidence for estrogen receptor mediation.
  55. (2002). Protective effects of estrogen and selective estrogen receptor modulators in the brain.
  56. (2007). Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis.
  57. (2000). Rat strain-specific actions of 17beta-estradiol in the mammary gland: correlation between estrogen-induced lobuloalveolar hyperplasia and susceptibility to estrogen-induced mammary cancers.
  58. (2005). Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance.
  59. (1985). Sixyear results of a controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer.
  60. (1998). Tamoxifen for early breast cancer: an overview of the randomised trials.
  61. (1998). Tamoxifen for prevention of breast cancer:
  62. (1995). Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: promotion by phenobarbital.
  63. (2005). The effects of tamoxifen and its metabolites on platelet function and release of reactive oxygen intermediates.
  64. (2006). The role of flavincontaining monooxygenase (FMO) in the metabolism of tamoxifen and other tertiary amines.
  65. (1998). The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen.
  66. (2009). Vitamin C and alphanaphthoflavone prevent estrogen-induced mammary tumors and decrease oxidative stress in female ACI rats.

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