Melatonin and breast cancer: cellular mechanisms, clinical studies and future perspectives

Abstract

Recent studies have suggested that the pineal hormone melatonin may protect against breast cancer, and the mechanisms underlying its actions are becoming clearer. Melatonin works through receptors and distinct second messenger pathways to reduce cellular proliferation and to induce cellular differentiation. In addition, independently of receptors melatonin can modulate oestrogen-dependent pathways and reduce free-radical formation, thus preventing mutation and cellular toxicity. The fact that melatonin works through a myriad of signalling cascades that are protective to cells makes this hormone a good candidate for use in the clinic for the prevention and/or treatment of cancer. This review summarises cellular mechanisms governing the action of melatonin and then considers the potential use of melatonin in breast cancer prevention and treatment, with an emphasis on improving clinical outcomes.

Figure 1. Mechanisms underlying the anticancer actions of melatonin

Melatonin can act through membrane-bound G-protein-coupled receptors (MT₁, MT₂), or in a receptor-independent manner. (a) Melatonin binding to its cell-surface receptors can activate Gi proteins (Giαβγ) to cause dissociation into Giα-GTP and Giβγ. Increases in Giα-GTP or Giβγ can affect the mitogen-activated protein kinase (MAPK) pathway. (b) In certain cell types, Giβγ may act via matrix metalloproteinases (MPs) to liberate heparin-bound EGF to activate EGFRs in an autocrine loop (Ref. 35). Subsequent activation of the downstream effectors MEKs and ERKs may drive cell proliferation or differentiation (hence dashed arrow) through nuclear events. (c) Also, activation of Gi may result in the internalisation of melatonin receptors and binding of β-arrestin-2 (probably to phosphorylated melatonin receptors) to activate MEKs and ERKs to target cytosolic proteins leading to differentiation. (d) Microtubules (purple rectangle) can directly bind to MEK/ ERK and modulate their activity and translocation patterns in a cell. (e) Besides effects on the MAPK pathway, activated Gi leads to the inhibition of adenylate cyclase (AC) via Giα-GTP to decrease cAMP levels within the cell. Decreases in cAMP leads to decreases in the transcription of genes responsive to oestrogen receptors (ERs). Gi can also be activated directly by microtubules to increase Giα-GTP through α–β tubulin heterodimers (not shown). (f) Melatonin can also act independently of melatonin receptors to drive cellular events, as it can easily traverse membranes. (g) It can inhibit the cytosolic protein calmodulin, which, in turn, can decrease adenylate cyclases sensitive to calmodulin (types I, III and VIII). Decreases in adenylate cyclase activity reduce cAMP levels to attenuate the transcription of ER-responsive genes. (h) Melatonin can also inhibit telomerase and aromatase to reduce cellular proliferation, and (i) can scavenge free radicals, thereby reducing oxidative damage. Other abbreviations: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular-signal-regulated kinase (also known as MAPK1); MEK, MAPK/ ERK kinase (also known as MAP2K1).

Figure 2. Clinical considerations for use of melatonin

As shown in this schematic, factors that disrupt the circadian rhythm (e.g. light at night, sleep deprivation, shift work, chronic jet lag and ageing) may increase susceptibility to oxidative damage through a suppression of the nocturnal melatonin surge (dotted line). The goal of therapy, then, would be to restore one’s nocturnal melatonin levels back to normal (solid line) by supplementing with melatonin at night (dosage still needs to be determined) and by reducing night-time light exposure.