title: Doxorubicin resistance in breast cancer is driven by light at night-induced disruption of the circadian melatonin signal.
abstract: 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 (ERα+) 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.
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Circadian Cancer Biology Group, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors: Shulin
authors: S
authors: Xiang
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Circadian Cancer Biology Group, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors: Robert T
authors: RT
authors: Dauchy
authors: Tulane Circadian Cancer Biology Group, New Orleans, LA, USA.|Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA.
authors: Adam
authors: A
authors: Hauch
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Circadian Cancer Biology Group, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors: Lulu
authors: L
authors: Mao
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Circadian Cancer Biology Group, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors: Lin
authors: L
authors: Yuan
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Circadian Cancer Biology Group, New Orleans, LA, USA.|Department of Comparative Medicine, Tulane University, New Orleans, LA, USA.
authors: Melissa A
authors: MA
authors: Wren
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Circadian Cancer Biology Group, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors: Victoria P
authors: VP
authors: Belancio
authors: Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA.
authors: Debasis
authors: D
authors: Mondal
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors: Tripp
authors: T
authors: Frasch
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Circadian Cancer Biology Group, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors: David E
authors: DE
authors: Blask
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.|Tulane Circadian Cancer Biology Group, New Orleans, LA, USA.|Tulane Center for Circadian Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors: Steven M
authors: SM
authors: Hill
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002940:Circadian Rhythm / Q000528:radiation effects*; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008027:Light; D061986:MCF-7 Cells; D008550:Melatonin / Q000378:metabolism*; D008819:Mice, Nude; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D004317:Doxorubicin; D005947:Glucose; D008550:Melatonin; D010100:Oxygen
keywords: breast; circadian; doxorubicin; melatonin; warburg