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Melatonin and Associated Signaling Pathways that Control Normal Breast Epithelium and Breast Cancer

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Abstract

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular and metabolic signaling mechanisms involved in human breast cancer growth and the associated consequences of circadian disruption by exposure to light-at-night (LAN). The anti-proliferative effects of the circadian melatonin signal are, in general, mediated through mechanisms involving the activation of MT1 melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor-positive (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT1-induced activation of Gαi2 signaling and reduction of cAMP levels. Melatonin also regulates the transcriptional activity of additional members of the nuclear receptor super-family, enzymes involved in estrogen metabolism, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and matrix metalloproteinase expression. Melatonin also inhibits the growth of human breast cancer xenografts via MT1-mediated suppression of cAMP leading to a blockade of linoleic acid (LA) uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Finally, studies in both rats and humans indicate that light-at-night (LAN) induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling, providing the strongest mechanistic support, thus far, for epidemiological studies demonstrating the elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.

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Abbreviations

LAN:

light at night

ERα:

estrogen receptor alpha

SCN:

suprachiasmatic nucleus

NR:

nuclear receptor

13-HODE:

13-hydroxyoctadecadienoic acid

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Acknowledgements

The work by the authors presented in this article was generously supported by National Institutes of Health grants 5R01CA054152-18 (SMH), Army Department Of Defense grant DAMD-123201 (SMH), National Institute of Environmental Health Sciences R21ES11659 (DEB), Edwin W. Pauley Foundation (DEB) and Grants for Laboratory Animal Science (GLAS) (RTD).

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Authors and Affiliations

  1. Department of Structural and Cellular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, LA, 70112, USA

    Steven M. Hill, David E. Blask, Shulin Xiang, Lin Yuan, Lulu Mao, Robert T. Dauchy, Erin M. Dauchy, Tripp Frasch & Tamika Duplesis

  2. Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, LA, 70112, USA

    Steven M. Hill, David E. Blask, Shulin Xiang, Lin Yuan, Lulu Mao, Robert T. Dauchy, Erin M. Dauchy & Tamika Duplesis

  3. Laboratory of Chrono-Neuroendocrine Oncology, Tulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, LA, 70112, USA

    David E. Blask, Robert T. Dauchy & Erin M. Dauchy

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  1. Steven M. Hill
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Correspondence to Steven M. Hill.

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Hill, S.M., Blask, D.E., Xiang, S. et al. Melatonin and Associated Signaling Pathways that Control Normal Breast Epithelium and Breast Cancer. J Mammary Gland Biol Neoplasia 16, 235–245 (2011). https://doi.org/10.1007/s10911-011-9222-4

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