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Disruption of circadian time structure and suppression of nocturnal melatonin production by dim light exposure at night (<jats:styled-content style=\"fixed-case\">dLEN<\/jats:styled-content>), as occurs with shift work, and\/or disturbed sleep\u2013wake 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\u2010activation of the receptor kinases <jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 and various other kinases and transcription factors. We demonstrate in tissue\u2010isolated estrogen receptor alpha\u2010positive (<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content><jats:italic>\u03b1<\/jats:italic>+) <jats:styled-content style=\"fixed-case\">MCF<\/jats:styled-content>\u20107 human breast cancer xenografts, grown in nude rats maintained on a light\/dark cycle of <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content> 12:12 in which <jats:styled-content style=\"fixed-case\">dLEN<\/jats:styled-content> is present during the dark phase (suppressed endogenous nocturnal melatonin), a significant shortening of tumor latency\u2010to\u2010onset, increased tumor metabolism and growth, and complete intrinsic resistance to Dox therapy. Conversely, a <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content> 12:12 <jats:styled-content style=\"fixed-case\">dLEN<\/jats:styled-content> environment incorporating nocturnal melatonin replacement resulted in significantly lengthened tumor latency\u2010to\u2010onset, 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\u2010regulated kinase inhibitor to reestablish the sensitivity of breast tumors to Dox and drive tumor regression, indicating that <jats:styled-content style=\"fixed-case\">dLEN<\/jats:styled-content>\u2010induced circadian disruption of nocturnal melatonin production contributes to a complete loss of tumor sensitivity to Dox chemotherapy.<\/jats:p>","DOI":"10.1111\/jpi.12239","type":"journal-article","created":{"date-parts":[[2015,4,7]],"date-time":"2015-04-07T15:39:51Z","timestamp":1428421191000},"page":"60-69","source":"Crossref","is-referenced-by-count":90,"title":["Doxorubicin resistance in breast cancer is driven by light at night\u2010induced disruption of the circadian melatonin signal"],"prefix":"10.1111","volume":"59","author":[{"given":"Shulin","family":"Xiang","sequence":"first","affiliation":[{"name":"Department of Structural and Cellular Biology Tulane University School of Medicine New Orleans LA 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