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

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

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.

Keywords

Melatonin Breast cancer Nuclear receptors Molecular signaling Circadian disruption Clock 

Abbreviations

LAN

light at night

ERα

estrogen receptor alpha

SCN

suprachiasmatic nucleus

NR

nuclear receptor

13-HODE

13-hydroxyoctadecadienoic acid

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Steven M. Hill
    • 1
    • 2
  • David E. Blask
    • 1
    • 2
    • 3
  • Shulin Xiang
    • 1
    • 2
  • Lin Yuan
    • 1
    • 2
  • Lulu Mao
    • 1
    • 2
  • Robert T. Dauchy
    • 1
    • 2
    • 3
  • Erin M. Dauchy
    • 1
    • 2
    • 3
  • Tripp Frasch
    • 1
  • Tamika Duplesis
    • 1
    • 2
  1. 1.Department of Structural and Cellular BiologyTulane University School of MedicineNew OrleansUSA
  2. 2.Tulane Cancer Center and Louisiana Cancer Research ConsortiumTulane University School of MedicineNew OrleansUSA
  3. 3.Laboratory of Chrono-Neuroendocrine OncologyTulane University School of MedicineNew OrleansUSA

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