Molecular Mechanisms of Melatonin Anticancer Effects

The authors have shown that,via activation of its MTI receptor, melatonin modulates the transcriptional activity of various nuclear receptors and the proliferation of both ER alpha+ and ER alpha- human breast cancer cells. Employing dominant-negative (DN) and dominant-positive (DP) G proteins, it was demonstrated that G alpha(12) proteins mediate the suppression of estrogen-induced ER alpha transcriptional activity by melatonin, whereas the G alpha(q) proteins mediate the enhancement of retinoid-induced RAR alpha. transcriptional activity by melatonin. In primary human breast tumors, the authors' studies demonstrate an inverse correlation between ER alpha and MTI receptor expression, and confocal microscopic studies demonstrate that the MTI receptor is localized to the caveoli and that its expression can be repressed by estrogen and melatonin. Melatonin, via activation of its MTI receptor, suppresses the development and growth of breast cancer by regulation of growth factors, regulation of gene expression, regulation of clock genes, inhibition of tumor cell invasion and metastasis, and even regulation of mammary gland development. The authors have previously reported that the clock gene, Period 2 (Per2), is not expressed in human breast cancer cells but that its reexpression in breast cancer cells results in increased expression of p53 and induction of apoptosis. The authors demonstrate that melatonin, via repression of ROR alpha transcriptional activity, blocks the expression of the clock gene WALL Melatonin's blockade of BMALI expression is associated with the decreased expression of SIRTI, a member of the Silencing Information Regulator family and a histone and protein deacetylase that inhibits the expression of DNA repair enzymes (p53, BRCA 1 & 2, and Ku70) and the expression of apoptosis-associated genes. Finally, the authors developed an MMTV-MTI-flag mammary knock-in transgenic mouse that displays reduced ductal branching, ductal epithelium proliferation, and reduced terminal end bud formation during puberty and pregnancy. Lactating female MTI transgenic mice show a dramatic reduction in the expression of beta-casein and whey acidic milk proteins. Further analyses showed significantly reduced ER alpha expression in mammary glands of MTI transgenic mice. These results demonstrate that the MTI receptor is a major transducer of melatonin's actions in the breast, suppressing mammary gland development and mediating the anticancer actions of melatonin through multiple pathways.