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

Authors

  • David E. Blask,

    1. Laboratory of Chrono-Neuroendocrine Oncology
    2. Department of Structural and Cellular Biology, Tulane University School of Medicine
    3. Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA
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  • Steven M. Hill,

    1. Department of Structural and Cellular Biology, Tulane University School of Medicine
    2. Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA
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  • Robert T. Dauchy,

    1. Laboratory of Chrono-Neuroendocrine Oncology
    2. Department of Structural and Cellular Biology, Tulane University School of Medicine
    3. Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA
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  • Shulin Xiang,

    1. Department of Structural and Cellular Biology, Tulane University School of Medicine
    2. Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA
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  • Lin Yuan,

    1. Department of Structural and Cellular Biology, Tulane University School of Medicine
    2. Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA
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  • Tamika Duplessis,

    1. Department of Structural and Cellular Biology, Tulane University School of Medicine
    2. Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA
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  • Lulu Mao,

    1. Department of Structural and Cellular Biology, Tulane University School of Medicine
    2. Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA
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  • Erin Dauchy,

    1. Laboratory of Chrono-Neuroendocrine Oncology
    2. Department of Structural and Cellular Biology, Tulane University School of Medicine
    3. Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA
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  • Leonard A. Sauer

    1. Laboratory of Chrono-Neuroendocrine Oncology
    2. Department of Structural and Cellular Biology, Tulane University School of Medicine
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Address reprint requests to David E. Blask, 1430 Tulane Avenue, SL-49, New Orleans, LA 70112, USA.
E-mail: dblask@tulane.edu

Abstract

Abstract:  This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary, and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light at night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT1 melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (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 3′,5′-cyclic adenosine monophosphate (cAMP) levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase, 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 the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT1-mediated suppression of cAMP leading to blockade of linoleic acid 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. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.

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