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Endocr Relat Cancer. 2015 Jun;22(3):R183-204. doi: 10.1530/ERC-15-0030. Epub 2015 Apr 15.

Melatonin: an inhibitor of breast cancer.

Author information

1
Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA smhill@tulane.edu.
2
Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA.
3
Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA.
4
Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA.

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:

breast cancer; circadian disruption; drug resistance; genomic instability; melatonin; molecular signaling; nuclear receptors

PMID:
25876649
PMCID:
PMC4457700
DOI:
10.1530/ERC-15-0030
[Indexed for MEDLINE]
Free PMC Article

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