Melatonin: an inhibitor of breast cancer

    1. David E Blask1,3,4,5
    1. 1Department of Structural and Cellular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USA
      2Department of Surgery,
      3Tulane Cancer Center and Louisiana Cancer Research Consortium,
      4Circadian Cancer Biology Group
      5Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
    1. Correspondence should be addressed to S M Hill; Email: smhill{at}tulane.edu

    Abstract

    The present review discusses recent work on melatonin-mediated circadian regulation, the metabolic and molecular signaling mechanisms that are involved in human breast cancer growth, and the associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin suppresses ERα mRNA expression and ERα transcriptional activity via the MT1 receptor. Melatonin also regulates the transactivation of other members of the nuclear receptor superfamily, estrogen-metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (the Warburg effect) and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type-specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways, including inhibition of p38 MAPK and repression of epithelial–mesenchymal transition (EMT). Studies have demonstrated that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models has indicated that LEN-induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer and drives breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms that underpin the epidemiologic demonstration of elevated breast cancer risk in night-shift workers and other individuals who are increasingly exposed to LEN.

    Keywords
    • Revision received 16 March 2015
    • Accepted 14 April 2015
    • Made available online as an Accepted Preprint 15 April 2015
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    1. Endocr Relat Cancer 22 R183-R204
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    3. All Versions of this Article:
      1. ERC-15-0030v1
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