Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2

Cancer Res. 2006 Aug 15;66(16):8293-6. doi: 10.1158/0008-5472.CAN-06-0300.

Abstract

Sulforaphane, a dietary isothiocyanate, possesses potent chemopreventive effects through the induction of cellular detoxifying/antioxidant enzymes via the transcription factor nuclear factor E2-related factor 2 (Nrf2). To investigate carcinogenesis mechanisms related to the regulation of Nrf2, we examined the tumor incidence and tumor numbers per mouse in Nrf2 wild-type (+/+) and Nrf2 knockout (-/-) mice. 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatments resulted in an increase in the incidence of skin tumors and tumor numbers per mouse in both genotypes; however, both indices were markedly higher in Nrf2(-/-) mice as compared with Nrf2(+/+) mice. Western blot analysis revealed that Nrf2 as well as heme oxygenase-1, a protein regulated by Nrf2 were not expressed in skin tumors from mice of either genotype, whereas expression of heme oxygenase-1 in Nrf2(+/+) mice was much higher than that in Nrf2(-/-) mice in nontumor skin samples. Next, we examined the chemopreventive efficacy of sulforaphane in mice with both genotypes. Topical application of 100 nmol of sulforaphane once a day for 14 days prior to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate applications decreased the incidence of skin tumor in the Nrf2(+/+) mice when compared with the vehicle-treated group. Importantly, there was no chemoprotective effect elicited by sulforaphane pretreatment in the Nrf2(-/-) mice group. Taken together, our results show for the first time that Nrf2(-/-) mice are more susceptible to skin tumorigenesis and that the chemopreventive effects of sulforaphane are mediated, at least in part, through Nrf2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity*
  • Animals
  • Anticarcinogenic Agents / therapeutic use*
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / isolation & purification
  • Disease Susceptibility
  • Isothiocyanates
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2 Transcription Factor / deficiency
  • NF-E2 Transcription Factor / genetics
  • NF-E2 Transcription Factor / physiology*
  • Polymerase Chain Reaction
  • Skin Neoplasms / chemically induced*
  • Skin Neoplasms / pathology
  • Skin Neoplasms / prevention & control*
  • Thiocyanates / therapeutic use*

Substances

  • Anticarcinogenic Agents
  • DNA, Neoplasm
  • Isothiocyanates
  • NF-E2 Transcription Factor
  • Thiocyanates
  • 9,10-Dimethyl-1,2-benzanthracene
  • sulforafan