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Author (up) Anbalagan, M.; Dauchy, R.; Xiang, S.; Robling, A.; Blask, D.; Rowan, B.; Hill, S.
Title SAT-337 Disruption Of The Circadian Melatonin Signal By Dim Light At Night Promotes Bone-lytic Breast Cancer Metastases Type Journal Article
Year 2019 Publication Journal of the Endocrine Society Abbreviated Journal
Volume 3 Issue Supplement_1 Pages
Keywords Human Health; Cancer; Breast cancer; melatonin; shift work; mouse models
Abstract Breast cancer metastasis to bone is a major source of morbidity and mortality in women with advanced metastatic breast cancer. Morbidity from metastasis to bone is compounded by the fact that they cannot be surgically removed and can only be treated with chemotherapy and/or radiation therapy. Thus, there is critical need to develop new treatment strategies that kill bone metastatic tumors and reduce osteolytic lesions to improve patient quality of life and extend patient survival. Circadian rhythms are daily cycles of ~24 h that control many if not most physiologic processes and their disruption by exposure to light at night (LAN) or jet lag has been shown to be strongly associated with the development of cancer, particularly breast cancer. We have found that disruption of the anti-cancer circadian hormone melatonin (MLT) by light at night can significantly enhance the metastatic potential in breast cancer cells. Our work supports the report of the International Agency for Research on Cancer that shift work is a “probable human carcinogen” and highlights the association between exposure to light at night and invasive breast cancer. We recently reported that human breast tumor xenografts grown in athymic nude female rats housed in a photoperiod of 12h light at day: 12h dim light at night (dLAN, 0.2 lux – blocks the nighttime circadian MLT signal), display resistance to doxorubicin (Dox). More importantly, tumor growth and drug resistance could be blocked by the administration of Dox in circadian alignment with nocturnal MLT during dLAN. Our recent preliminary studies show that poorly invasive ERα positive MCF-7 breast cancer cells, when injected into the tibia (to mimic bone metastatic disease) of Foxn1nu athymic nude mice (which produce a strong circadian nighttime melatonin signal) housed in a dLAN photoperiod (suppressed nocturnal MLT production) developed full blown breast cancer tumors in bone (P<0.05) that are highly osteolytic (P<0.05). Moreover, patients with metastatic breast cancer are routinely treated with doxorubicin, which itself can promote bone damage. Our studies demonstrate that MLT slows the growth of metastatic breast cancer in bone but that the chrono-therapeutic use of doxorubicin in circadian alignment with melatonin in Foxn1nu mice with tibial breast tumors, reduced tumor growth in bone, reduced bone erosion, and promoted the formation of new bone. Successful use of this chronotherapeutic use of Dox and MLT in clinical trials increasing efficacy in preventing or suppressing breast cancer metastasis to bone while decreasing toxic side effects of doxorubicin would provide a revolutionary advancement in the treatment of bone metastatic breast cancer and decrease the morbidity and mortality associated with breast cancer metastasis to bone.
Address Tulane University School of Medicine, New Orleans, LA, United States
Corporate Author Thesis
Publisher Oxford Academic Place of Publication Editor
Language English Summary Language English Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 2472-1972 ISBN Medium
Area Expedition Conference
Notes Approved no
Call Number GFZ @ kyba @ Serial 2433
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Author (up) Dauchy, R.T.; Xiang, S.; Mao, L.; Brimer, S.; Wren, M.A.; Yuan, L.; Anbalagan, M.; Hauch, A.; Frasch, T.; Rowan, B.G.; Blask, D.E.; Hill, S.M.
Title Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer Type Journal Article
Year 2014 Publication Cancer Research Abbreviated Journal Cancer Res
Volume 74 Issue 15 Pages 4099-4110
Keywords *Cancer; breast cancer; melatonin; endocrinology; tamoxifen; *Circadian Rhythm; circadian disruption; human health; epidemiology
Abstract Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to antiestrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of estrogen receptor (ERalpha(+)) MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speed the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characteristics were not observed in animals in which the circadian melatonin rhythm was not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen. Cancer Res; 74(15); 4099-110. (c)2014 AACR.
Address Departments of Structural and Cellular Biology and Tulane Cancer Center and Louisiana Cancer Research Consortium; Tulane Circadian Cancer Biology Group; and
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0008-5472 ISBN Medium
Area Expedition Conference
Notes PMID:25062775; PMCID:PMC4119539 Approved no
Call Number IDA @ john @ Serial 355
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Author (up) deHaro, D.; Kines, K.J.; Sokolowski, M.; Dauchy, R.T.; Streva, V.A.; Hill, S.M.; Hanifin, J.P.; Brainard, G.C.; Blask, D.E.; Belancio, V.P.
Title Regulation of L1 expression and retrotransposition by melatonin and its receptor: implications for cancer risk associated with light exposure at night Type Journal Article
Year 2014 Publication Nucleic Acids Research Abbreviated Journal Nucleic Acids Res
Volume 42 Issue 12 Pages 7694-7707
Keywords Human Health
Abstract Expression of long interspersed element-1 (L1) is upregulated in many human malignancies. L1 can introduce genomic instability via insertional mutagenesis and DNA double-strand breaks, both of which may promote cancer. Light exposure at night, a recently recognized carcinogen, is associated with an increased risk of cancer in shift workers. We report that melatonin receptor 1 inhibits mobilization of L1 in cultured cells through downregulation of L1 mRNA and ORF1 protein. The addition of melatonin receptor antagonists abolishes the MT1 effect on retrotransposition in a dose-dependent manner. Furthermore, melatonin-rich, but not melatonin-poor, human blood collected at different times during the circadian cycle suppresses endogenous L1 mRNA during in situ perfusion of tissue-isolated xenografts of human cancer. Supplementation of human blood with exogenous melatonin or melatonin receptor antagonist during the in situ perfusion establishes a receptor-mediated action of melatonin on L1 expression. Combined tissue culture and in vivo data support that environmental light exposure of the host regulates expression of L1 elements in tumors. Our data imply that light-induced suppression of melatonin production in shift workers may increase L1-induced genomic instability in their genomes and suggest a possible connection between L1 activity and increased incidence of cancer associated with circadian disruption.
Address Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane Cancer Center, New Orleans, LA 70115, USA Tulane Center for Aging, New Orleans, LA 70112, USA vperepe@tulane.edu
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0305-1048 ISBN Medium
Area Expedition Conference
Notes PMID:24914052; PMCID:PMC4081101 Approved no
Call Number LoNNe @ kyba @ Serial 1414
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Author (up) Hanifin, J.P.; Dauchy, R.T.; Blask, D.E.; Hill, S.M.; Brainard, G.C.
Title Relevance of Electrical Light on Circadian, Neuroendocrine, and Neurobehavioral Regulation in Laboratory Animal Facilities Type Journal Article
Year 2020 Publication ILAR Journal Abbreviated Journal
Volume in press Issue Pages
Keywords Review; Animals
Abstract Light is a key extrinsic factor to be considered in operations and design of animal room facilities. Over the past four decades, many studies on typical laboratory animal populations have demonstrated impacts on neuroendocrine, neurobehavioral, and circadian physiology. These effects are regulated independently from the defined physiology for the visual system. The range of physiological responses that oscillate with the 24 hour rhythm of the day include sleep and wakefulness, body temperature, hormonal secretion, and a wide range of other physiological parameters. Melatonin has been the chief neuroendocrine hormone studied, but acute light-induced effects on corticosterone as well as other hormones have also been observed. Within the last two decades, a new photosensory system in the mammalian eye has been discovered. A small set of retinal ganglion cells, previously thought to function as a visual output neuron, have been shown to be directly photosensitive and act differently from the classic photoreceptors of the visual system. Understanding the effects of light on mammalian physiology and behavior must take into account how the classical visual photoreceptors and the newly discovered ipRGC photoreceptor systems interact. Scientists and facility managers need to appreciate lighting impacts on circadian, neuroendocrine, and neurobehavioral regulation in order to improve lighting of laboratory facilities to foster optimum health and well-being of animals.
Address
Corporate Author Thesis
Publisher Place of Publication Editor
Language Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1084-2020 ISBN Medium
Area Expedition Conference
Notes Approved no
Call Number GFZ @ kyba @ Serial 3024
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Author (up) Mason, I.C.; Boubekri, M.; Figueiro, M.G.; Hasler, B.P.; Hattar, S.; Hill, S.M.; Nelson, R.J.; Sharkey, K.M.; Wright, K.P.; Boyd, W.A.; Brown, M.K.; Laposky, A.D.; Twery, M.J.; Zee, P.C.
Title Circadian Health and Light: A Report on the National Heart, Lung, and Blood Institute's Workshop Type Journal Article
Year 2018 Publication Journal of Biological Rhythms Abbreviated Journal J Biol Rhythms
Volume 33 Issue 5 Pages 451-457
Keywords Human Health
Abstract Despite the omnipresence of artificial and natural light exposure, there exists little guidance in the United States and elsewhere on light exposure in terms of timing, intensity, spectrum, and other light characteristics known to affect human health, performance, and well-being; in parallel, there is little information regarding the quantity and characteristics of light exposure that people receive. To address this, the National Center on Sleep Disorders Research, in the Division of Lung Diseases, National Heart, Lung, and Blood Institute, held a workshop in August 2016 on circadian health and light. Workshop participants discussed scientific research advances on the effects of light on human physiology, identified remaining knowledge gaps in these research areas, and articulated opportunities to use appropriate lighting to protect and improve circadian-dependent health. Based on this workshop, participants put forth the following strategic intent, objectives, and strategies to guide discovery, measurement, education, and implementation of the appropriate use of light to achieve, promote, and maintain circadian health in modern society.
Address Center for Circadian and Sleep Medicine, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0748-7304 ISBN Medium
Area Expedition Conference
Notes PMID:30033850 Approved no
Call Number GFZ @ kyba @ Serial 1975
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Author (up) Xiang, S.; Dauchy, R.T.; Hoffman, A.E.; Pointer, D.; Frasch, T.; Blask, D.E.; Hill, S.M.
Title Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3-driven paclitaxel resistance in breast cancer Type Journal Article
Year 2019 Publication Journal of Pineal Research Abbreviated Journal J Pineal Res
Volume 67 Issue 2 Pages e12586
Keywords Animals; Human Health; Circadian Rhythm; Cancer; tumor suppression
Abstract Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) production by exposure to dim light at night (dLAN), as occurs with night shift work and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of breast cancer and resistance to tamoxifen and doxorubicin. Melatonin inhibition of human breast cancer chemo-resistance involves mechanisms including suppression of tumor metabolism and inhibition of kinases and transcription factors which are often activated in drug-resistant breast cancer. Signal Transducer and Activator of Transcription 3 (STAT3), frequently overexpressed and activated in Paclitaxel (PTX)-resistant breast cancer, promotes the expression of DNA methyltransferase one (DNMT1) to epigenetically suppresses the transcription of tumor suppressor Aplasia Ras homolog one (ARHI) which can sequester STAT3 in the cytoplasm to block PTX-resistance. We demonstrate that breast tumor xenografts in rats exposed to dLAN and circadian MLT disrupted express elevated levels of phosphorylated and acetylated STAT3, increased DNMT1, but reduced Sirtuin 1 (SIRT1) and ARHI. Furthermore, MLT and/or SIRT1 administration blocked/reversed Interleukin 6 (IL-6)-induced acetylation of STAT3 and its methylation of ARH1 to increase ARH1 mRNA expression in MCF-7 breast cancer cells. Finally, analyses of the I-SPY 1 trial demonstrates that elevated MT1 receptor expression is significantly correlated with pathologic complete response following neo-adjuvant therapy in breast cancer patients. This is the first study to demonstrate circadian disruption of MLT by dLAN driving intrinsic resistance to PTX via epigenetic mechanisms increasing STAT3 expression and that MLT administration can reestablish sensitivity of breast tumors to PTX and drive tumor regression.
Address Tulane Circadian Cancer Biology Group, New Orleans, Louisiana
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0742-3098 ISBN Medium
Area Expedition Conference
Notes PMID:31077613 Approved no
Call Number GFZ @ kyba @ Serial 2383
Permanent link to this record