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Cancer Res. 2014 Aug 1;74(15):4099-110. doi: 10.1158/0008-5472.CAN-13-3156.

Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer.

Author information

1
Departments of Structural and Cellular Biology and Tulane Circadian Cancer Biology Group; and.
2
Departments of Structural and Cellular Biology and Tulane Cancer Center and Louisiana Cancer Research Consortium; Tulane Circadian Cancer Biology Group; and.
3
Surgery, Tulane University School of Medicine;
4
Departments of Structural and Cellular Biology and Tulane Circadian Cancer Biology Group; and Department of Comparative Medicine, Tulane University, New Orleans, Louisiana.
5
Surgery, Tulane University School of Medicine; Tulane Circadian Cancer Biology Group; and.
6
Departments of Structural and Cellular Biology and tfrasch@tulane.edu.

Abstract

Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to antiestrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of estrogen receptor (ERα(+)) MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speed the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characteristics were not observed in animals in which the circadian melatonin rhythm was not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen.

PMID:
25062775
PMCID:
PMC4119539
DOI:
10.1158/0008-5472.CAN-13-3156
[Indexed for MEDLINE]
Free PMC Article
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