Matthew Tjahja

Introduction: Breast cancer is the most common cancer in the United States representing nearly 14.6% of all new cancer cases². Melatonin is both an output and modulator/regulator of the central circadian clock. Several circadian clock genes such as period genes (Per1 and Per2) have decreased expression in sporadic and familiar breast tumors. Per1 and Per2 have tumor suppressor functions that operate in a circadian pattern. Melatonin modulates and regulates peripheral oscillators in tissues such as the breast thus resynchronizing dysregulated clock genes like Per1 and Per2⁸. Studies have indicated that decreased expression melatonin can lead to increased proliferation in breast tissue due to lack of activity of the MT1 receptor⁴. Other studies have shown that melatonin supplementation in mice exposed to circadian-disrupting dim light exposure at night (dLEN) greatly diminishes expression or activation of tumor-promoting kinases and transcription factors³. These findings suggest melatonin supplementation as a possible adjunctive therapy for breast cancer prophylaxis and prevention. Methods: Rats with ERa MCF-7 breast tumor xenografts were exposed to different light/dark cycles with dLEN in order to disrupt intrinsic melatonin production. Once tumors weighed 8g, were out 40 days past implantation, or regressed to 1.6g they were prepared for in situ tumor vein cannulation. Arterial glucose, lactate, acid/gas, fatty acids, and melatonin were analyzed³. Results: Rats exposed to dLEN had an increased development of breast tumors, increased metabolism and growth, and intrinsic resistance to tamoxifen therapy when compared to animals in which the circadian melatonin rhythm was not disrupted or animals who had melatonin replacement³. Conclusions: Numerous studies have demonstrated the oncostatic and oncorepressive characteristics of melatonin. Over the counter melatonin supplementation in humans could provide a novel chronotherapeutic approach to breast cancer therapy and prevention¹. Possible mechanisms of action for breast cancer suppression include DNA methylation, p53 acetylation and activation, fatty acid metabolism, and the Warburg effect^1,3,5-7. Furthermore, recent studies have even implicated melatonin, endogenous or exogenous, as a necessary adjunct to tamoxifen therapy.

1. Blask DE, Dauchy RT, Dauchy EM, Hill SM, Mao L, Wren MM, Meyaski-Schluter MMC, Yuan L. Over-the-counter melatonin supplementation in human subjects: A potentially novel chronotherapeutic approach targeting the Warburg effect and fatty acid metabolism in breast cancer therapy/prevention. [abstract]. Proceedings of the AACR Special Conference: Metabolism and Cancer; 2015 Jun 7-10.
2. “Breast Cancer Screening (PDQÒ)-Health Professional Version.”- National Cancer Institute. National Institute of Health, 2017 Feb 22. Web. 20 Mar. 2017.
3. Dauchy RT, Xiang S, Mao L, Brimer S, Wren MA, Yuan L, Anbalagan M, Hauch A, Frasch T, Rowan BG, Blask DE, Hill SM. Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer. Cancer Research. 2014 Aug; 74 (15).
4. Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, Hauch A, Lundburg PW, Summers W, Yuan L, Frasch T, Blask DE. Melatonin: an inhibitor of breast cancer. Endocrine-Related Cancer. 2015 Jun 1; 22 R183-R204.
5. Hill SM, Blask DE “Effects of the Pineal Hormone Melatonin on the Proliferation and Morphological Characteristics of Human Breast Cancer Cells (MCF-7) in Culture. Cancer Research. 1988 Nov. 1. 48: 6121-6126. Web. 21 Mar. 2017.
6. Lee, S. E., Kim, S. J., Yoon, H.-J., Yu, S. Y., Yang, H., Jeong, S. I., Hwang, S. Y., Park, C.-S. and Park, Y. S. (2013), Genome-wide profiling in melatonin-exposed human breast cancer cell lines identifies differentially methylated genes involved in the anticancer effect of melatonin. J. Pineal Res., 54: 80–88.
7. Proietti, S., Cucina, A., Dobrowolny, G., D’Anselmi, F., Dinicola, S., Masiello, M. G., Pasqualato, A., Palombo, A., Morini, V., Reiter, R. J. and Bizzarri, M. (2014), Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells. Journal of Pineal Research, 57: 120–129.
8. Savvidis C, Koutsilieris M. “Circadian Rhythm Disruption in Cancer Biology.” Molecular Medicine. 2012 Jul. 17; 18: 1249-1260. Web. 20 Mar. 2017