Abstract LB-212: Circadian melatonin signal disruption by exposure to artificial light at night promotes bone lytic breast cancer metastases

Abstract

Abstract Breast cancer (BC) metastasis to bone is most common in patients with advanced metastatic BC. Erosion of bone by BC metastases increases bone fragility, risk of fracture and mortality in BC patients. Bone metastatic BC cannot be surgically removed and can only be treated with chemotherapy and/or radiation therapy. Circadian rhythms are daily cycles of ~24 h that control most physiologic processes, disruption of these processes by exposure to artificial light at night (LAN) has been shown to be strongly associated with the development of cancer, particularly breast cancer. Disruption (suppression) of melatonin (MLT) production by LAN is considered as a risk factor for BC. The present study addressed the hypothesis that circadian MLT disruption by dim LAN (dLAN) promotes osteolytic bone metastatic BC. Our research shows that the disruption of the anti-cancer circadian hormone MLT signaling by exposure to dLAN can significantly enhance the metastatic potential of BC cells. This supports the report of the International Agency for Research on Cancer that night shift work is a “probable human carcinogen” and highlights the association between exposure to LAN and invasive BC. We have previously reported that human breast tumor xenografts grown in athymic nude female rats housed in a photoperiod of 12h light at day:12h dLAN (suppressed melatonin 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. Our present results show that moderately metastatic luminal A estrogen receptor alpha (ERα) positive MCF-7 BC cells, when inoculated into the tibia (to mimic bone metastatic disease) of MLT-producing Foxn1nu athymic nude mice and housed in dLAN (suppressed nocturnal melatonin production), developed robust bone metastatic tumors (P<0.05) that were highly osteolytic (P<0.05) as determined by IVIS bioluminescent imaging, x-ray and µCT analysis. Administration of nighttime MLT at physiological levels was able to partially reduce the bone metastatic tumor burden. The MLT receptor (MT1 and MT2) antagonist luzindole blocked the inhibitory effect of nighttime MLT on bone metastatic tumor growth supporting a receptor-mediated mechanism. These findings demonstrate for the first time the importance of intact nighttime MLT anti-cancer signaling in suppressing bone metastatic breast tumor growth. Our results provide a potentially strong conceptual rationale for the development of a unique clinical strategy to improve the survival rates of bone metastatic BC patients with the use of circadian-optimized MLT therapy. Acknowledgements: Supported in part by U54 GM104940 from the National Institute of General Medical Sciences of the NIH, which funds the Louisiana Clinical and Translational Science Center (LACATS). Citation Format: Muralidharan Anbalagan. Circadian melatonin signal disruption by exposure to artificial light at night promotes bone lytic breast cancer metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-212.