The present review discusses recent work on
melatonin-mediated circadian regulation, the metabolic and molecular signaling mechanisms that are involved in human
breast cancer growth, and the associated consequences of circadian disruption by exposure to light at night (LEN). The anti-
cancer actions of the circadian
melatonin signal in human
breast cancer cell lines and xenografts heavily involve
MT1 receptor-mediated mechanisms. In
estrogen receptor alpha (ERα)-positive human
breast cancer,
melatonin suppresses ERα
mRNA expression and ERα transcriptional activity via the
MT1 receptor.
Melatonin also regulates the transactivation of other members of the
nuclear receptor superfamily,
estrogen-metabolizing
enzymes, and the expression of core clock and clock-related genes. Furthermore,
melatonin also suppresses
tumor aerobic metabolism (the Warburg effect) and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival,
metastasis, and drug resistance.
Melatonin demonstrates both
cytostatic and cytotoxic activity in
breast cancer cells that appears to be cell type-specific.
Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways, including inhibition of
p38 MAPK and repression of epithelial-mesenchymal transition (EMT). Studies have demonstrated that
melatonin promotes
genomic stability by inhibiting the expression of LINE-1
retrotransposons. Finally, research in animal and human models has indicated that LEN-induced disruption of the circadian nocturnal
melatonin signal promotes the growth, metabolism, and signaling of human
breast cancer and drives
breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms that underpin the epidemiologic demonstration of elevated
breast cancer risk in night-shift workers and other individuals who are increasingly exposed to LEN.