Even dim light exposure during nighttime hours hastens tumor growth and tamoxifen resistance, according to a new xenograft study.
Exposure to dim light at night hastens breast tumor growth and resistance to tamoxifen, according to a newly published study of rats with estrogen receptor (ERα)–positive MCF-7 human breast cancer xenografts.1
The findings “have potential implications for the large number of patients with breast cancer who are being treated with tamoxifen, because they suggest that nighttime exposure to light, even dim light, could cause their tumors to become resistant to the drug by suppressing melatonin production,” said senior study author Steven M. Hill, PhD, of Tulane University School of Medicine in New Orleans, Louisiana. Dr. Hill is the director of the Tulane Center for Circadian Biology.
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“Our data suggest that [patients with] breast cancer should sleep in a dark room (or use a sleeping mask) and try to make sure they stay in the dark for at least 8 hours” per night, Dr. Hill told Cancer Therapy Advisor.
The new study compared breast cancer xenografts in rats kept in normal light conditions—12 hours of light followed by 12 hours of complete darkness—with breast cancer xenograft in rats kept in 12 hours of normal light followed by 12 hours of dim light. Tumor growth in rats living in dim-light conditions at night was 2.6 times as fast as that seen among animals kept in normal light conditions.
But when exogenous melatonin was administered at night in animals exposed to dim light, “the tumors become sensitive to tamoxifen, cells die[d] and the tumors regress[ed],” Dr. Hill said.
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The scientists reported their findings in Cancer Research.1
Based on these results and that of previous studies, the authors believe that melatonin is both a tumor metabolism inhibitor and a circadian-regulated kinase inhibitor that can reestablish a breast tumors’ sensitivity to tamoxifen.
Tamoxifen resistance has been a growing problem among patients with hormone receptor–positive breast cancer, Dr. Hill noted.
The laboratory rats used in the study are a nocturnal species but melatonin metabolism follows the same light/dark cycle in nocturnal and diurnal species as humans. “Even though they are awake at night, their blood melatonin levels increase at night,” Dr. Hill noted. Other studies have shown that nocturnal rodents’ melatonin production is dependent on light—rather than sleep.2
Is Timing Everything?
Maximizing the efficacy of tamoxifen therapy will probably turn out to depend partly on “optimal temporal administration” to match the circadian cycle of patients with nonlight-disrupted sleep or the timing of exogenous melatonin administration in patients with disrupted circadian light/dark cycles, the researchers noted.
It’s too soon to recommend melatonin supplements for women undergoing tamoxifen therapy, Dr. Hill said. Taking melatonin supplements at the wrong time of day could possibly disrupt the circadian system, which could “paradoxically impair breast cancer responsiveness to tamoxifen,” he cautioned.
But women who are taking tamoxifen and who are also already taking melatonin as a sleep aid at night, don’t need to stop taking melatonin supplements, Dr. Hill said. Bedtime administration likely prolongs the body’s natural melatonin production, he noted, “which according to our studies, will slow the growth of cancer cells.”
There are “few if any” studies that indicate significant toxicities associated with melatonin, he said.
However, the timing of tamoxifen administration may also be important. To find out if that’s the case, Dr. Hill’s team plans to use the same human breast tumor xenograft animal model to determine if the observed synergy between melatonin and tamoxifen is lost or decreased when tamoxifen is administered at times other than the body’s natural after-dark melatonin production.
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A growing number of studies indicate that circadian cycle disruption from reduced sleep or nighttime light exposure can increase the risk (and worsen prognosis) for cancer and that the body’s circadian clock and cell division cycles are driven by shared genes, including c-Myc and p21.3
In 2008, the World Health Organization classified extended late-night shift work as a possible carcinogen for breast cancer, Dr. Hill noted.
“We are working toward a proof-of-principle clinical trial in women with breast cancer to validate that the changes we see in melatonin-inhibiting tumor metabolism and cancer-signaling pathways in human breast tumors in rats, are also [seen] in women with breast cancer,” he said.
“It is plausible that many, if not all, patients with breast cancer are likely to be subjected to various degrees of light exposure at night and may be circadian/melatonin disrupted as a result of lack of sleep and/or chronic late-night shift work,” Dr. Hill and his coauthors noted. “Therefore, light exposure at night might represent a unique and previously unappreciated risk factor that could account for some forms of intrinsic and possibly acquired tamoxifen resistance and may even lead to a shortened survival time and a decreased survival rate.”
References
- Dauchy RT, Xiang S, Mao L, et al. Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer. Cancer Res. 2014;74(15):4099-4110.
- Bilu C, Kronfeld-Schor N. Effects of circadian phase and melatonin injection on anxiety-like behavior in nocturnal and diurnal rodents. Chronobiol Int. 2013;30(6):828-836.
- Kelleher FC, Rao A, Maguire A. Circadian molecular clocks and cancer. Cancer Lett. 2014;342(1):9-18.
