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

Abstract

Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to anti-estrogen 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 ERα+ MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speeds the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characters were not produced in animals where circadian rhythms were 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 re-establish 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.

Melatonin, an inhibitory agent in breast cancer

“…Following this study, in 1997, Bartsch and his colleagues reported a reverse correlation between melatonin concentrations and the tumor progression rate, suggesting that the urine amount of 6-sulfatoxymelatonin (melatonin metabolite) is lower in women suffering from breast cancer compared to healthy volunteers [9]. Further clinical investigations pointed out a reverse correlation between decrease nocturnal melatonin plasma level and the incidence of estrogen receptor positive type breast cancer, suggesting the administration of melatonin may be particularly advantageous to these patients [10][11][12]. Moreover, it has been established that disrupt the circadian rhythm of the melatonin level by some factors, including light at night, sleep deprivation, shift work, chronic jet lag, mutations in melatonin genes and ageing may increase susceptibility of normal breast cells to oxidative damages, leading to an increased risk of breast cancer mostly through elevated secretion of the activated cytokines [13].…”

Emerging functional roles of nuclear receptors in breast cancer

“…The oncostatic effect of melatonin in breast cancer is thought be mediated through its anti-estrogenic actions as well as its role in regulating the activity of aromatases, the enzymes responsible for the local biosynthesis of estrogens from androgens (Cos et al 2006). Recent studies using MCF-7 breast cancer xenografts in mice showed that suppression of melatonin production by dim light exposure at night leads to both tamoxifen (Dauchy et al 2014) and doxorubicin resistance (Xiang et al 2015).…”

Putative Links Between Sleep Apnea and Cancer

“…In fact, we are not aware of specifi c assessments of SF in patient cohorts and cancer, although there is substantial indirect evidence from studies demonstrating that long-term night workers and shift workers have increased incidence of solid malignancies 59,60 that appear to be attributable, at least partly, to reduced melatonin secretion. [61][62][63] Similarly, the cumulative evidence gathered thus far would suggest that sleep duration is an important factor in cancer incidence and outcomes. In a series of meta-analyses, shift work was strongly associated with a higher risk of breast cancer, [64][65][66] but most if not all the studies had major sociodemographic factors and comorbidity confounders (including obesity and metabolic disease).…”