Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night

Abstract

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light-at-night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT1 melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT1-induced activation of Gαi2 signaling and reduction of cAMP levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT1-mediated suppression of cAMP leading to blockade of linoleic acid (LA) uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.

Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data

“…It has also been shown that melatonin at physiological levels suppresses the proliferation of human breast cancer xenografts (15)(16)(17). Furthermore, melatonin may reduce the invasiveness of human breast cancer, and the suppression of melatonin during the biological night may act as a promoter of oncogenesis (10,16). This experimental evidence suggests that suppression of melatonin from night shift work may exert its response downstream the complex casual pathways that lead to breast cancer.…”

“…From animal studies it is known that melatonin reduces the growth of chemically induced mammary tumors (10,14). It has also been shown that melatonin at physiological levels suppresses the proliferation of human breast cancer xenografts (15)(16)(17). Furthermore, melatonin may reduce the invasiveness of human breast cancer, and the suppression of melatonin during the biological night may act as a promoter of oncogenesis (10,16).…”

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

“…In these recent studies, the addition of MLT to the drinking water blocked the accelerated tumor growth effects of ALAN. In rodent models of tumorigeneses, the metastasis formation of solid tumors increased in response to pinealectomy and induced-metastatic surgery effect, whereas pharmacological MLT administration reversed the formation [201]. In MCF-7 human breast-cancer cell lines, MLT administration reduced the tumor invasion potential [202], and in MCF-7 tumor-bearing mice, MLT lessened metastasis formation compared with counterpart untreated mice [203].…”

“…MLT can affect breast cancer cell development by blocking the linoleic acid uptake via MT1-induced cyclic adenosine monophosphate (cAMP) suppression; this promotes the downregulation of the mitogenic signaling molecule 13-hydroxyoctadecadienoic that is responsible for the activation of growth factor pathways that are essential for cells growth and survival [201]. MLT can modulate the expression patterns of different core clock genes and other circadian-related genes involved in cellular carcinogenic activities [209].…”

“…Two membrane G-protein associated coupled receptors, MT1 and MT2, are expressed across many tissues and cells in the body and have been found to mediate most of the oncostatic responses to MLT [207]. The MLT-induced oncostatic activities in ERα+ MCF-7 human breast-cancer cells are mediated mainly by the MT1 receptor, which is coupled with several G-proteins, including Gα i2 , Gα i3 , Gα q , and Gα 11 [201].…”