Chemotherapeutic resistance, particularly to
doxorubicin (Dox), represents a major impediment to successfully treating
breast cancer and is linked to elevated
tumor metabolism and
tumor over-expression and/or activation of various families of receptor- and non-receptor-associated
tyrosine kinases. Disruption of circadian time structure and suppression of nocturnal
melatonin production by dim light exposure at night (dLEN), as occurs with shift work, and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of an array of diseases, including
breast cancer.
Melatonin inhibits human
breast cancer growth via mechanisms that include the suppression of
tumor metabolism and inhibition of expression or phospho-activation of the receptor
kinases AKT and ERK1/2 and various other
kinases and
transcription factors. We demonstrate in tissue-isolated
estrogen receptor alpha-positive (ERĪ±+) MCF-7 human
breast cancer xenografts, grown in nude rats maintained on a light/dark cycle of LD 12:12 in which dLEN is present during the dark phase (suppressed endogenous nocturnal
melatonin), a significant shortening of
tumor latency-to-onset, increased
tumor metabolism and growth, and complete intrinsic resistance to Dox
therapy. Conversely, a LD 12:12 dLEN environment incorporating nocturnal
melatonin replacement resulted in significantly lengthened
tumor latency-to-onset,
tumor regression, suppression of nighttime
tumor metabolism, and
kinase and
transcription factor phosphorylation, while Dox sensitivity was completely restored.
Melatonin acts as both a
tumor metabolic inhibitor and circadian-regulated
kinase inhibitor to reestablish the sensitivity of
breast tumors to Dox and drive
tumor regression, indicating that dLEN-induced circadian disruption of nocturnal
melatonin production contributes to a complete loss of
tumor sensitivity to Dox
chemotherapy.