Carcinogenesis Advance Access published online on July 4, 2003
Carcinogenesis, doi:10.1093/carcin/bgg103
© 2003 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 American Health Foundation Cancer Center, Institute for Cancer Prevention, 1 Dana Road, Valhalla, NY 10595
* Corresponding author. E-mail: kelbayou{at}ifcp.us.
Received 31 March 2003
; revised 2 June 2003
; accepted 14 June 2003
We employed cDNA microarray analysis to identify, in mammary adenocarcinomas induced by 7,12-dimethylbenz[a]anthracene [DMBA] in the rat, target genes as potential biomarkers for cancer chemoprevention by 1,4-phenylenebis(methylene)selenocyanate [p-XSC]. Confirmation of selected genes was conducted by reverse transcription polymerase chain reactions [RT-PCR]. The glutathione conjugate, p-XSeSG, a putative metabolite of p-XSC was also employed to test our hypothesis that p-XSeSG is a more effective cancer chemopreventive agent in the mammary cancer model than p-XSC. Mammary adenocarcinomas were induced by a single oral administration of 5 mg DMBA in 0.2 ml olive oil per rat at 50-55 days of age. Consistent with our previous reports, dietary p-XSC at a non-toxic dose (10 ppm as selenium) significantly inhibited adenocarcinoma development, independent of feeding duration. Moreover, p-XSeSG appears to be just as effective as p-XSC when fed after DMBA administration, but was significantly less effective than p-XSC in inhibiting the induction of mammary adenocarcinomas when it was fed before DMBA and continued until termination. To delineate the molecular basis for cancer chemoprevention by organoselenium compounds, we focused our analysis on differential expression of genes known to be involved in DMBA metabolism, as well as those related to cell cycle, cell proliferation, and apoptosis. p-XSC and p-XSeSG were significantly and equally effective in inhibiting levels of expression of genes associated with cytochrome P450 isoforms, but the former was more active than the latter in upregulating the expression of those related to certain phase II enzymes. p-XSC and p-XSeSG were significantly more effective in the upregulation of pro-apoptotic genes, such as p21CIP1/WAF1, p27KIP1, APO-1, and Caspase-3, while downregulating cell growth regulatory genes, such as c-myc, cyclin D1, cyclin D2 and proliferating cell nuclear antigen (PCNA). To our knowledge, this is the first report that provides insights into the effects of p-XSC and p-XSeSG at the molecular level that may account for mammary cancer chemoprevention in vivo in the rat.
Elucidation of molecular targets of mammary cancer chemoprevention in the rat by organoselenium compounds using cDNA microarray
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