Abstract
Disturbed sleep-wake cycle and circadian rhythmicity are associated with cancer, but the underlying mechanisms are unknown. Employing a tissue-isolated human breast xenograft tumor nude rat model, we observed that glycogen synthase kinase 3β (GSK3β), an enzyme critical in metabolism and cell proliferation/survival, exhibits a circadian rhythm of phosphorylation in human breast tumors. Exposure to light-at-night suppresses the nocturnal pineal melatonin synthesis, disrupting the circadian rhythm of GSK3β phosphorylation. Melatonin activates GSK3β by inhibiting the serine-threonine kinase Akt phosphorylation, inducing β-catenin degradation and inhibiting epithelial-to-mesenchymal transition, a fundamental process underlying cancer metastasis. Thus, chronic circadian disruption by light-at-night via occupational exposure or age-related sleep disturbances may contribute to cancer incidence and the metastatic spread of breast cancer by inhibiting GSK3β activity and driving epithelial-to-mesenchymal transition in breast cancer patients.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / enzymology*
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Breast Neoplasms / pathology*
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Breast Neoplasms / physiopathology
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Cell Line, Tumor
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Circadian Rhythm* / drug effects
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Circadian Rhythm* / radiation effects
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Enzyme Activation / drug effects
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Enzyme Activation / radiation effects
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Epithelial-Mesenchymal Transition* / drug effects
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Epithelial-Mesenchymal Transition* / radiation effects
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Female
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Glycogen Synthase Kinase 3 / metabolism*
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Glycogen Synthase Kinase 3 beta
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Humans
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Light
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Male
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Melatonin / metabolism*
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Melatonin / pharmacology
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Models, Biological
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Phosphorylation / drug effects
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Phosphorylation / radiation effects
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Phosphoserine / metabolism
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / pathology
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Prostatic Neoplasms / physiopathology
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Snail Family Transcription Factors
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Transcription Factors / metabolism
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Xenograft Model Antitumor Assays
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Young Adult
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beta Catenin / metabolism
Substances
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Snai2 protein, rat
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Snail Family Transcription Factors
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Transcription Factors
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beta Catenin
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Phosphoserine
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, rat
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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Melatonin