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Chemopreventive Doses of Methylselenocysteine Alter Circadian Rhythm in Rat Mammary Tissue

Authors' Affiliations: ¹ Division of Human Biology, Fred Hutchinson Cancer Research Center; ² Department of Environmental and Occupational Health, University of Washington, Seattle, Washington; and ³ Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey

Requests for reprints: Helmut Zarbl, Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, EOHSI, 170 Freylinghuysen Road, Room 426, Piscataway, NJ, 08854. Phone: 732-445-2354; E-mail: zarbl{at}eohsi.rutgers.edu.

It is known that organic forms of selenium inhibit chemically induced rat mammary carcinogenesis, although the molecular basis remains to be elucidated. To identify signaling pathways involved in carcinogenesis that are also modulated by methylselenocysteine, we compared the global gene expression profiles in mammary tissues from pubescent female rats maintained on a selenium-supplemented (3 ppm) diet with those on a standardized diet after N-nitroso-N-methylurea. Whereas the selenium-enriched diet altered the steady-state levels of genes involved in various cellular functions, the most dramatic effect was the coordinated changes in the expression of multiple genes that regulate circadian rhythm. Normal mammary tissue of rats fed a standardized diet showed little circadian oscillation relative to liver tissue. By contrast, mammary tissue of rats maintained on the selenium-enriched diet showed a progressive, time-dependent increase in the expression of circadian gene Per2 and circadian-regulated transcription factor DBP. Our results further showed that the expression of Per2 and DBP mRNAs was significantly decreased in mammary tumors arising in rats on the selenium-enriched diet, but not in tumors of rats on the control diet, suggesting that selenium-induced elevation in the expression of circadian genes was incompatible with mammary carcinogenesis. Given the previously reported role of Per2 as a tumor suppressor, these observations suggest that Per2 is an important target of methylselenocysteine during chemoprevention in N-nitroso-N-methylurea–induced rat mammary carcinogenesis, and for the first time provide a link between chemoprevention and circadian rhythm.

Key Words: selenium • chemoprevention • mammary carcinogenesis • microarray • circadian