Abstract 4897: Circadian/melatonin disruption by dim light at night drives human epithelial breast cancer to a metastatic phenotype

Abstract

Cancer patients with disrupted 24-hour (circadian) rhythms are reported to have poorer survival as compared to those with normal rhythms. Severe alterations in circadian rhythms predict an increased risk of death in patients with colorectal and breast cancer, suggesting that circadian disruption may impact tumor progression and metastasis. We recently reported that circadian/melatonin (MLT) disruption by exposure to dim light at night (dLAN) resulted in constitutive phospho-activation of ERK1/2, CREB, NF-kB, and STAT3 in breast tumor xenografts promoting resistance to Tamoxifen and Doxorubicin therapy. Given that chemoresistant breast cancer is frequently metastatic, this study examined if dLAN-induced circadian/MLT disruption can promote epithelial-to- mesenchymal transition (EMT) of epithelial MCF-7 breast tumor xenografts leading to the development of metastatic foci in the lungs, livers, and brains of circadian complete (MLT-producing) athymic nude female rats and mice. Female nude rats with ERα+ MCF-7 or T47D human epithelial breast cancer xenografts were housed in LD,12:12 and LD,12:12dLAN (dLAN) photoperiods or in dLAN supplemented with nighttime MLT (0.05 µg/ml) in the drinking water, with lights on at 0600 hrs and off at 1800 hrs. Blood samples collected during the mid-dark phase (2400 hrs) showed elevated nocturnal melatonin (118.4 pg/ml) in the LD,12:12 group, but significantly suppressed melatonin (10.0 pg/ml) in the dLAN group. Tumor xenografts from rats housed in dLAN showed a ~3-fold decrease in latency-to-onset and a ~2.8-fold increase in growth rates vs. those from rats in dLAN + MLT. Tumor cAMP levels, as well as numerous signaling pathways involved in promoting EMT (Vimentin, β-catenin, and SNAIL) and metastasis (HER2/HER3, pCREB, pERK1/2, pRSK2, and pSTAT3), showed increased expression/phospho-activation at 2400 hrs in response to dLAN but repressed expression in tumors from rats in dLAN + MLT. Follow-up studies with Foxn1nude female mice implanted with non-metastatic luciferase expressing MCF-7 breast cancer cells showed that exposure to dLAN suppressed the nighttime serum levels of MLT by 93% in these mice compared to those in a LD,12:12 photoperiod. Exposure of mice to dLAN induced the rapid growth of MCF-7luc tumor xenografts and, after 5 weeks, induced the metastatic outgrowth of MCF-7 xenografts to form luciferase identifiable metastatic foci in the lungs, livers, and brains of all mice, as measured by IVIS small animal imaging system. Conversely, MCF-7luc tumor xenografts from mice exposed to dLAN and supplemented with nighttime MLT showed a reduced tumor development, 3-fold slower tumor growth, and a small metastatic lesion in one lung of a single mouse. This study is the first to show that circadian/MLT disruption by host exposure to dLAN is able to drive EMT in human epithelial breast cancer xenografts to generate metastatic foci in lung, liver, and brain of mice. Citation Format: Steven M. Hill, Shulin Xiang, Robert T. Dauchy, Melissa Wren-Dail, Murali Anbalagan, Brian Rowan, Tripp Frasch, David E. Blask. Circadian/melatonin disruption by dim light at night drives human epithelial breast cancer to a metastatic phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4897. doi:10.1158/1538-7445.AM2017-4897

Light Pollution and Cancer

“…Xenografts perfused with melatonin-rich blood displayed suppressed proliferative activity compared to xenografts perfused with melatonin-deficient blood, thereby demonstrating that melatonin may be antioncogenic and that modulation of the hormone by light exposure is sufficient to alter proliferation [157]. Likewise, disruption of melatonin rhythms via exposure to ALAN lead to metastatic developments in the lung, liver, and brain of athymic nude rats with ERα+ MCF-7 breast cancer xenografts, whereas administration of exogenous melatonin reduced tumor development and metastatic lesions [158]. Moreover, exposure to artificial LAN promoted osteolytic bone metastases in MCF-7-bearing mice, and administration of melatonin during the inactive period reduced tumor burden in bone metastases, whereas luzindole (melatonin receptor antagonist) blocked the inhibitory effect [159].…”

Artificial Light at Night Reduces Anxiety-like Behavior in Female Mice with Exacerbated Mammary Tumor Growth

“…In addition, disruption of melatonin rhythms via exposure to ALAN can lead to an increased number of metastases. Indeed, housing nude mice in ALAN led to increased metastatic developments in the lung, liver, and brain [ 60 ]. Administration of exogenous melatonin reduced tumor burden and the number of metastatic lesions, which, while not explicitly tested, appeared to suggest that the increased growth seen in the current study was likely due to suppressed melatonin rhythms via exposure to ALAN.…”