Our laboratory has shown that melatonin significantly inhibits the proliferation of ER+, but not ER- human breast cancer cells, and modulates the expression and transcriptional activity of the ERa. We have also demonstrated that melatonin can cross-talk with the retinoic acid (RA) signaling pathway, such that, when treated with a regimen of melatonin followed by RA at physiologic doses, breast cancer cells undergo apoptosis. In vivo, the combination of melatonin and 9-cis-RA was shown to be significantly more effective than RA alone at inhibiting the development and inducing the regression of carcinogen-induced rat mammary tumors. Furthermore, we have developed new data showing that melatonin's effects in tumor cells are mediated via the Mella/mt1 G protein-coupled receptor, and that overexpression of this receptor can enhance the response of ER+ breast tumor cells to the growth inhibitory effects of melatonin. These data led to our current hypothesis that the growth-inhibitory actions of melatonin are mediated, at least in part, through the Mella/mt1 melatonin receptor via modulation of the transcriptional activity of steroid/thyroid hormone receptor signaling pathways (ERa and RAR/RXR), and that overexpression of the Mella/mt1 receptor can generate a melatonin supersensitive phenotype in ER+ breast cancer cells. To test this hypothesis, we have developed the following Specific Aims: (1) To elucidate the importance of the Mella/mt1 receptor in the development and progression of breast cancer, and the signaling pathway(s) utilized by the Mel la/mt1 receptor to suppress MCF-7 cell proliferation; (2) To define the importance of the Mella/mt1 receptor in controlling breast cancer cell growth using Mel I a/mt1 gene ablation and transgenic overexpression techniques; (3) To determine if MCF-7 cells overexpressing the Mella/mtl receptor exhibit an enhanced response to the timed regimen of melatonin and RA, and to delineate further the interaction/cross-talk between melatonin and RA signaling pathways in regulating MCF-7 cell proliferation and apoptosis; and (4) To determine the optimal retinoid, dosage, and time period for the regimen of melatonin and RA which induces maximal regression of N-nitrosomethylurea (NMU)-induced rat mammary tumors. The characterization of the pathways by which melatonin inhibits the development and growth of breast tumors, and cross-talks with other hormone response pathways, such as the estrogen and retinoid pathways, is essential for the development of future endocrine strategies in the treatment and prevention of breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Jhappan, Chamelli
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Tulane University
Anatomy/Cell Biology
Schools of Medicine
New Orleans
United States
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Blask, David E; Dauchy, Robert T; Dauchy, Erin M et al. (2014) Light exposure at night disrupts host/cancer circadian regulatory dynamics: impact on the Warburg effect, lipid signaling and tumor growth prevention. PLoS One 9:e102776
Mao, Lulu; Yuan, Lin; Xiang, Shulin et al. (2014) Molecular deficiency (ies) in MT? melatonin signaling pathway underlies the melatonin-unresponsive phenotype in MDA-MB-231 human breast cancer cells. J Pineal Res 56:246-53
Hill, Steven M; Cheng, Chi; Yuan, Lin et al. (2013) Age-related decline in melatonin and its MT1 receptor are associated with decreased sensitivity to melatonin and enhanced mammary tumor growth. Curr Aging Sci 6:125-33
Xiang, Shulin; Mao, Lulu; Yuan, Lin et al. (2012) Impaired mouse mammary gland growth and development is mediated by melatonin and its MT1G protein-coupled receptor via repression of ER?, Akt1, and Stat5. J Pineal Res 53:307-18
Xiang, S; Mao, L; Duplessis, T et al. (2012) Oscillation of clock and clock controlled genes induced by serum shock in human breast epithelial and breast cancer cells: regulation by melatonin. Breast Cancer (Auckl) 6:137-50
Mao, Lulu; Dauchy, Robert T; Blask, David E et al. (2012) Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3?. Mol Endocrinol 26:1808-20
Blask, David E; Hill, Steven M; Dauchy, Robert T et al. (2011) Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night. J Pineal Res 51:259-69
Hill, Steven M; Cheng, Chi; Yuan, Lin et al. (2011) Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin. Breast Cancer Res Treat 127:91-8
Hill, Steven M; Blask, David E; Xiang, Shulin et al. (2011) Melatonin and associated signaling pathways that control normal breast epithelium and breast cancer. J Mammary Gland Biol Neoplasia 16:235-45
Mao, Lulu; Yuan, Lin; Slakey, Lauren M et al. (2010) Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of the p38 mitogen-activated protein kinase signaling pathway. Breast Cancer Res 12:R107

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