Steven M. Hill
Tulane University School of Medicine, USA
Title: Circadian/melatonin disruption by dim light at night drives human epithelial breast cancer to a metastatic phenotype
Biography
Biography: Steven M. Hill
Abstract
Cancer patients with disrupted 24-hour (circadian) rhythms are reported to have poorer survival as compared to those with normal rhythms. We have reported that circadian/melatonin (MLT) disruption by exposure to dim light at night (dLAN) resulted in constitutive activation of ERK1/2, STAT3, and signaling nodes involved in epithelial to mesenchymal transition (EMT) in breast tumor xenografts promoting drug-resistance and that MLT can suppress the invasive activity of metastatic breast cancer. This study examined the scientific premise that dLAN-induced circadian/MLT disruption promotes 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. Employing athymic nude female rats and mice with ERa+ MCF-7 luciferase expressing tumor xenografts housed in LD, 12:12 (nighttime MLT) and LD, 12:12dLAN (dLAN) photoperiods or in dLAN supplemented with night time MLT, tumor from rats in dLAN showed increased growth and expression of signaling nodes involved in promoting EMT and metastasis vs. those from rats in LD: 12:12 dLAN+MLT or LD, 12:12. Nude mice exposed to dLAN showed metastatic outgrowth of MCF-7Luc xenografts forming identifiable metastatic foci in the lungs, livers, and brains of all mice, which was inhibited by MLT, as measured by IVIS small animal imaging system. CRISPR knock out of the MT1 MLT receptor in MCF-7 breast cancer cells induced a 9-fold increase in invasion as compared to parental control cells. This study is the first to show that circadian/MLT disruption by dLAN cab drive EMT and metastasis.