Abstract: Breast cancer metastasis to bone is a major source of morbidity and mortality in women with advanced metastatic breast cancer. Morbidity from metastasis to bone is compounded by the fact that they cannot be surgically removed and can only be treated with chemotherapy and/or radiation therapy. Thus, there is critical need to develop new treatment strategies that kill bone metastatic tumors and reduce osteolytic lesions to improve patient quality of life and extend patient survival. Circadian rhythms are daily cycles of ~24 h that control many if not most physiologic processes and their disruption by exposure to light at night (LAN) or jet lag has been shown to be strongly associated with the development of cancer, particularly breast cancer. We have found that disruption of the anti-cancer circadian hormone melatonin (MLT) by light at night can significantly enhance the metastatic potential in breast cancer cells. Our work supports the report of the International Agency for Research on Cancer that shift work is a “probable human carcinogen” and highlights the association between exposure to light at night and invasive breast cancer. We recently reported that human breast tumor xenografts grown in athymic nude female rats housed in a photoperiod of 12h light at day: 12h dim light at night (dLAN, 0.2 lux – blocks the nighttime circadian MLT signal), display resistance to doxorubicin (Dox). More importantly, tumor growth and drug resistance could be blocked by the administration of Dox in circadian alignment with nocturnal MLT during dLAN. Our recent preliminary studies show that poorly invasive ERα positive MCF-7 breast cancer cells, when injected into the tibia (to mimic bone metastatic disease) of Foxn1nu athymic nude mice (which produce a strong circadian nighttime melatonin signal) housed in a dLAN photoperiod (suppressed nocturnal MLT production) developed full blown breast cancer tumors in bone (P<0.05) that are highly osteolytic (P<0.05). Moreover, patients with metastatic breast cancer are routinely treated with doxorubicin, which itself can promote bone damage. Our studies demonstrate that MLT slows the growth of metastatic breast cancer in bone but that the chrono-therapeutic use of doxorubicin in circadian alignment with melatonin in Foxn1nu mice with tibial breast tumors, reduced tumor growth in bone, reduced bone erosion, and promoted the formation of new bone. Successful use of this chronotherapeutic use of Dox and MLT in clinical trials increasing efficacy in preventing or suppressing breast cancer metastasis to bone while decreasing toxic side effects of doxorubicin would provide a revolutionary advancement in the treatment of bone metastatic breast cancer and decrease the morbidity and mortality associated with breast cancer metastasis to bone.

Abstract: It has frequently been reported that exposure to artificial light at night (ALAN) may cause negative health effects, such as breast cancer, circadian phase disruption and sleep disorders. Here, we reviewed the literature assessing the effects of human exposure to ALAN in order to list the health effects of various aspects of ALAN. Several electronic databases were searched for articles, published through August 2014, related to assessing the effects of exposure to ALAN on human health; these also included the details of experiments on such exposure. A total of 85 articles were included in the review. Several observational studies showed that outdoor ALAN levels are a risk factor for breast cancer and reported that indoor light intensity and individual lighting habits were relevant to this risk. Exposure to artificial bright light during the nighttime suppresses melatonin secretion, increases sleep onset latency (SOL) and increases alertness. Circadian misalignment caused by chronic ALAN exposure may have negative effects on the psychological, cardiovascular and/or metabolic functions. ALAN also causes circadian phase disruption, which increases with longer duration of exposure and with exposure later in the evening. It has also been reported that shorter wavelengths of light preferentially disturb melatonin secretion and cause circadian phase shifts, even if the light is not bright. This literature review may be helpful to understand the health effects of ALAN exposure and suggests that it is necessary to consider various characteristics of artificial light, beyond mere intensity.

Abstract: Exposure to light at night may increase the risk of breast cancer by suppressing the normal nocturnal production of melatonin by the pineal gland, which, in turn, could increase the release of estrogen by the ovaries. This study investigated whether such exposure is associated with an increased risk of breast cancer in women. Methods: Case patients (n = 813), aged 20–74 years, were diagnosed from November 1992 through March 1995; control subjects (n = 793) were identified by random-digit dialing and were frequency matched according to 5-year age groups. An in-person interview was used to gather information on sleep habits and bedroom lighting environment in the 10 years before diagnosis and lifetime occupational history. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by use of conditional logistic regression, with adjustment for other potential risk factors. Results: Breast cancer risk was increased among subjects who frequently did not sleep during the period of the night when melatonin levels are typically at their highest (OR = 1.14 for each night per week; 95% CI = 1.01 to 1.28). Risk did not increase with interrupted sleep accompanied by turning on a light. There was an indication of increased risk among subjects with the brightest bedrooms. Graveyard shiftwork was associated with increased breast cancer risk (OR = 1.6; 95% CI = 1.0 to 2.5), with a trend of increased risk with increasing years and with more hours per week of graveyard shiftwork (P = .02, Wald chi-squared test). Conclusion: The results of this study provide evidence that indicators of exposure to light at night may be associated with the risk of developing breast cancer.

Abstract: PURPOSE: Shift work, short sleep duration, employment as a flight attendant, and exposure to light at night, all potential causes of circadian disruption, have been inconsistently associated with breast cancer (BrCA) risk. The aim of this meta-analysis is to quantitatively evaluate the combined and independent effects of exposure to different sources of circadian disruption on BrCA risk in women. METHODS: Relevant studies published through January 2014 were identified by searching the PubMed database. The pooled relative risks (RRs) and corresponding 95 % confidence intervals (CIs) were estimated using fixed- or random effects models as indicated by heterogeneity tests. Generalized least squares trend test was used to assess dose-response relationships. RESULTS: A total of 28 studies, 15 on shift work, 7 on short sleep duration, 3 on flight attendants, and 6 on light at night were included in the analysis. The combined analysis suggested a significantly positive association between circadian disruption and BrCA risk (RR = 1.14; 95 % CI 1.08-1.21). Separate analyses showed that the RR for BrCA was 1.19 (95 % CI 1.08-1.32) for shift work, 1.120 (95 % CI 1.119-1.121) for exposure to light at night, 1.56 (95 % CI 1.10-2.21) for employment as a flight attendant, and 0.96 (95 % CI 0.86-1.06) for short sleep duration. A dose-response analysis showed that each 10-year increment of shift work was associated with 16 % higher risk of BrCA (95 % CI 1.06-1.27) based on selected case-control studies. No significant dose-response effects of exposure to light at night and sleep deficiency were found on BrCA risk. CONCLUSIONS: Our meta-analysis demonstrates that circadian disruption is associated with an increased BrCA risk in women. This association varied by specific sources of circadian disrupting exposures, and a dose-response relationship remains uncertain. Therefore, future rigorous prospective studies are needed to confirm these relationships.

Abstract: Excessive exposure to artificial light at night (ALAN) suppresses nocturnal melatonin (MLT) production in the pineal gland and is, therefore, associated with an increased risk of breast cancer (BC). We examined indoor and outdoor light habits of 278 women, BC patients (n = 93), and controls (n = 185; 2010-2014). Cases and controls were age and residential area matched. Data regarding behavior in the sleeping habitat in a 5-year period, 10 to 15 years prior to disease diagnosis, were collected using a questionnaire. Sleep quality, bedtime, sleep duration, TV watching habits, presleeping reading habits, subjective illumination intensity, and type of illumination were collected. Binary logistic regression models were used to calculate odds ratios with 95% confidence intervals (ORs with 95% CIs) for BC patients in relation to those habits. OR results revealed that women who had slept longer (controls), 10 to 15 years before the time of the study, in a period of 5 years, had a significant (OR = 0.74; 95% CI = 0.57-0.97; P < .03) reduced BC risk. Likewise, women who had been moderately exposed to ALAN as a result of reading using bed light (reading lamp) illumination and women who had slept with closed shutters reduced their BC risk: OR = 0.81, 95% CI = 0.67-0.97, P < .02, and OR = 0.82, 95% CI = 0.68-0.99, P < .04, respectively. However, women who had been exposed to ALAN as a result of living near strong illumination sources were at a significantly higher BC risk (OR = 1.52; 95% CI = 1.10-2.12; P < .01). These data support the hypothesis that diminishing nighttime light exposure will diminish BC risk and incidence. This hypothesis needs to be tested directly using available testing strategies and technologies that continuously measure an individual's light exposure, its timing, and sleep length longitudinally and feed this information back to the individual, so that BC risk can be distinguished prospectively.