Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer

Jul 27, 2014Cancer research

Nighttime light exposure disrupts body clock and melatonin, leading to natural resistance to tamoxifen treatment in breast cancer

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Abstract

Altering light/dark cycles with dim light exposure at night (dLEN) accelerates breast tumor development in a rat model.

Disruption of melatonin production by dLEN is linked to increased metabolism and growth of breast tumors.
Breast tumors developed under dLEN conditions showed intrinsic resistance to tamoxifen therapy.
No resistance to tamoxifen was observed in rats with intact circadian melatonin rhythms or those receiving nocturnal melatonin replacement.
Melatonin functions as both a tumor metabolic inhibitor and a kinase inhibitor, restoring sensitivity to tamoxifen.
Disturbances in nocturnal melatonin production due to dLEN may contribute to treatment resistance in breast cancer.

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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.

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Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer

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