Melatonin and Associated Signaling Pathways that Control Normal Breast Epithelium and Breast Cancer

Abstract

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular and metabolic signaling mechanisms involved in human breast cancer growth and the associated consequences of circadian disruption by exposure to light-at-night (LAN). The anti-proliferative effects of the circadian melatonin signal are, in general, mediated through mechanisms involving the activation of MT(1) melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor-positive (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT(1)-induced activation of G(αi2) signaling and reduction of cAMP levels. Melatonin also regulates the transcriptional activity of additional members of the nuclear receptor super-family, enzymes involved in estrogen metabolism, 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 matrix metalloproteinase expression. Melatonin also inhibits the growth of human breast cancer xenografts via MT(1)-mediated suppression of cAMP leading to a 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. Finally, studies in both rats and humans indicate that light-at-night (LAN) induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling, providing the strongest mechanistic support, thus far, for epidemiological studies demonstrating the elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…The repression of the nocturnal circadian melatonin signal promotes tumor aerobic glycolysis and the expression and activation of the signaling pathways involved in tumor proliferation and survival that drive resistance in cancer cells to endocrine therapies and chemotherapies [40]. Therefore, the melatonin signal regulates metabolic and cell signaling activities to inhibit cancer initiation, promotion, and progression [162], and these effects can be mediated by melatonin MT 1 /MT 2 receptors [163].…”

Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium

“…Moreover, preclinical in vitro and in vivo studies and clinical trials showed that melatonin was able to exert an oncostatic action on different tumors (Girgert et al, 2009;Hill et al, 2009Hill et al, , 2011aJung and Ahmad, 2006;Sánchez-Barceló et al, 2012;Srinivasan et al, 2008), to increase the efficacy of chemotherapy when used in adjuvant settings and to decrease the side effects (Vijayalaxmi et al, 2002). Since proliferation and differentiation are typical of any cell system and are carefully regulated in the course of physiological development and life cycle, tumor evolution must imply a deregulation of their morphofunctional features.…”

Determinants of vitamin D status among Jordanian employees: Focus on the night shift effect

“…Our results showed a positive correlation between age and serum 25OHD levels for both the males and females. Age was shown to be positively associated with 25OHD levels in previous reports [15,55]. Lower serum 25OHD levels in younger individuals has been suggested to be associated with their lower forearm bone mineral content [15].…”

“…A number of factors have been found to be associated with low 25OHD levels. These factors include, among others, low sun exposure, age, obesity, smoking, dress style in the case of women and physical activity [5,[13][14][15][16][17][18][19][20]. In the absence of adequate sun exposure, 25OHD levels may be insufficient to achieve the desired physiologic role [5,[21][22][23][24].…”