Abstract
<div>Abstract<p>Epidemiologic and animal studies indicate that disruption of circadian rhythm increases breast cancer risk. Previously, we showed that methylselenocysteine reduced the incidence of <i>N</i>-nitroso-<i>N</i>-methylurea (NMU)–induced mammary carcinomas in Fischer 344 rats by 63%. Methylselenocysteine also increased the expression of <i>Period 2</i> (<i>Per2</i>) and <i>D-binding protein</i> (<i>DBP</i>), providing evidence for a link between circadian rhythm and chemoprevention. Here, we report that NMU disrupted the expression of core circadian genes (<i>Per1, Per2, Cry1, Cry2,</i> and <i>RevErbAα</i>) and circadian-controlled genes, including <i>melatonin receptor 1α</i> (<i>MTNR1A</i>), estrogen receptors (<i>ERα</i> and <i>ERβ</i>), and growth-regulatory genes (<i>Trp53, p21, Gadd45α</i>, and <i>c-Myc</i>) in mammary glands of Fischer 344 rats. By contrast, dietary methylselenocysteine (3 ppm selenium) given for 30 days, significantly enhanced the circadian expression of these genes (except for <i>Cry1</i> and <i>Cry2</i>). The largest effect was on the levels of the <i>Per2, MTNR1A</i>, and <i>ERβ</i> mRNAs, which showed 16.5-fold, 4.7-fold, and 9.5-fold increases in their rhythm-adjusted means, respectively, and 44.5-fold, 6.5-fold, and 9.7-fold increases in amplitude as compared with the control diet, respectively. Methylselenocysteine also shifted the peak expression times of these genes to Zeitgeber time 12 (ZT12; lights off). Methylselenocysteine also induced rhythmic expression of <i>Trp53, p21</i>, and <i>Gadd45α</i> mRNAs with peak levels at ZT12, when <i>c-Myc</i> expression was at its lowest level. However, methylselenocysteine had no significant effect on the circadian expression of these genes in liver. These results suggest that dietary methylselenocysteine counteracted the disruptive effect of NMU on circadian expression of genes essential to normal mammary cell growth and differentiation. Cancer Prev Res; 3(5); 640–52. ©2010 AACR.</p></div>
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