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Journal of Mammary Gland Biology and Neoplasia
Published in: Journal of Mammary Gland Biology and Neoplasia 3/2011

01-09-2011

Melatonin and Associated Signaling Pathways that Control Normal Breast Epithelium and Breast Cancer

Authors: Steven M. Hill, David E. Blask, Shulin Xiang, Lin Yuan, Lulu Mao, Robert T. Dauchy, Erin M. Dauchy, Tripp Frasch, Tamika Duplesis

Published in: Journal of Mammary Gland Biology and Neoplasia | Issue 3/2011

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Abstract

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular and metabolic signaling mechanisms involved in human breast cancer growth and the associated consequences of circadian disruption by exposure to light-at-night (LAN). The anti-proliferative effects of the circadian melatonin signal are, in general, mediated through mechanisms involving the activation of MT1 melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor-positive (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT1-induced activation of Gαi2 signaling and reduction of cAMP levels. Melatonin also regulates the transcriptional activity of additional members of the nuclear receptor super-family, enzymes involved in estrogen metabolism, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and matrix metalloproteinase expression. Melatonin also inhibits the growth of human breast cancer xenografts via MT1-mediated suppression of cAMP leading to a blockade of linoleic acid (LA) uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Finally, studies in both rats and humans indicate that light-at-night (LAN) induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling, providing the strongest mechanistic support, thus far, for epidemiological studies demonstrating the elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.
Literature
1.
Brainard GC, Hanifin JP, Greeson JM, et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci. 2001;21:6405–12.PubMed
2.
Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science. 2002;295:1070–3.PubMedCrossRef
3.
Hastings M, Reddy AB, Maywood ES. A clockwork web: circadian timing in brain and periphery, in health and disease. Nat Rev Neurosci. 2003;4:649–61.PubMedCrossRef
4.
Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005;9:11–24.PubMedCrossRef
5.
6.
Stevens RG, Blask DE, Brainard GC, et al. Meeting report: the role of environmental lighting and circadian disruption in cancer and other diseases. Environ Health Perspect. 2007;115:1357–62.PubMedCrossRef
7.
8.
You S, Wood PA, Xiong Y, et al. Daily coordination of cancer growth and circadian clock gene expression. Breast Cancer Res Treat. 2005;91:47–60.PubMedCrossRef
9.
Kohsaka A, Bass J. A sense of time: how molecular clocks organize metabolism. Trends Endocrinol Metab. 2007;18:4–11.PubMedCrossRef
10.
Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine. 2005;27:179–88.PubMedCrossRef
11.
Hill SM, Blask DE. Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res. 1988;48:6121–6.PubMed
12.
Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem. 2002;2:113–32.PubMedCrossRef
13.
Cos S, Blask DE, Lemus-Wilson A, et al. Effects of melatonin on the cell cycle kinetics and “estrogen-rescue” of MCF-7 human breast cancer cells in culture. J Pineal Res. 1991;10:36–42.PubMedCrossRef
14.
Hill SM, Frasch T, Xiang S, et al. Molecular mechanisms of melatonin anticancer effects. Integr Cancer Ther. 2009;8:337–46.PubMedCrossRef
15.
Blask DE, Brainard GC, Dauchy RT, et al. Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res. 2005;65:11174–84.PubMedCrossRef
16.
Brydon L, Roka F, Petit L, et al. Dual signaling of human Mel1a melatonin receptors via G(i2), G(i3), and G(q/11) proteins. Mol Endocrinol. 1999;13:2025–38.PubMedCrossRef
17.
Lai L, Yuan L, Chen Q, et al. The Galphai and Galphaq proteins mediate the effects of melatonin on steroid/thyroid hormone receptor transcriptional activity and breast cancer cell proliferation. J Pineal Res. 2008;45:476–88.PubMedCrossRef
18.
Collins A, Yuan L, Kiefer TL, et al. Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice. Cancer Lett. 2003;189:49–57.PubMedCrossRef
19.
Yuan L, Collins AR, Dai J, et al. MT(1) melatonin receptor overexpression enhances the growth suppressive effect of melatonin in human breast cancer cells. Mol Cell Endocrinol. 2002;192:147–56.PubMedCrossRef
20.
Lai L, Yuan L, Cheng Q, et al. Alteration of the MT1 melatonin receptor gene and its expression in primary human breast tumors and breast cancer cell lines. Breast Cancer Res Treat. 2009;118:293–305.PubMedCrossRef
21.
Molis TM, Spriggs LL, Hill SM. Modulation of estrogen receptor mRNA expression by melatonin in MCF-7 human breast cancer cells. Mol Endocrinol. 1994;8:1681–90.PubMedCrossRef
22.
Ram PT, Kiefer T, Silverman M, et al. Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors. Mol Cell Endocrinol. 1998;141:53–64.PubMedCrossRef
23.
Hill SM, Frasch T, Xiang S, Yuan L, et al. Molecular mechanisms of melatonin anticancer effects. Integr Cancer Res. 2009;8:337–46.CrossRef
24.
Del Rio B, Garcia Pedrero JM, Martinez-Campa C, et al. Melatonin, an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin. J Biol Chem. 2004;279:38294–302.PubMedCrossRef
25.
Dai J, Inscho EW, Yuan L, et al. Modulation of intracellular calcium and calmodulin by melatonin in MCF-7 human breast cancer cells. J Pineal Res. 2002;32:112–9.PubMedCrossRef
26.
Kiefer TL, Lai L, Yuan L, et al. Differential regulation of estrogen receptor alpha, glucocorticoid receptor and retinoic acid receptor alpha transcriptional activity by melatonin is mediated via different G proteins. J Pineal Res. 2005;38:231–9.PubMedCrossRef
27.
Dai J, Ram PT, Yuan L, et al. Transcriptional repression of RORalpha activity in human breast cancer cells by melatonin. Mol Cell Endocrinol. 2001;176:111–20.PubMedCrossRef
28.
Lapin V. Pineal gland and malignancy. Osterr Z Onkol. 1976;3:51–60.PubMed
29.
Blask DE. The pineal: an oncostatic gland? In: Rj R, editor. The pineal gland. New York: Raven; 1984. p. 253–84.
30.
Cos S, Fernandez R, Guezmes A, et al. Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res. 1998;58:4383–90.PubMed
31.
Leon-Blanco MM, Guerrero JM, Reiter RJ, et al. Melatonin inhibits telomerase activity in the MCF-7 tumor cell line both in vivo and in vitro. J Pineal Res. 2003;35:204–11.PubMedCrossRef
32.
Tan M, Yao J, Yu D. Overexpression of the c-erbB-2 gene enhanced intrinsic metastasis potential in human breast cancer cells without increasing their transformation abilities. Cancer Res. 1997;57:1199–205.PubMed
33.
Schmid BC, Rudas M, Rezniczek GA, et al. CXCR4 is expressed in ductal carcinoma in situ of the breast and in atypical ductal hyperplasia. Breast Cancer Res Treat. 2004;84:247–50.PubMedCrossRef
34.
Mao L, Slakey LM, Jones FE, Burow ME, Hill SM. Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of p38 mitogen-activated protien kinase signaling pathway. Breast Cancer Res. 2010;12:R107 Epub.
35.
Kim MS, Lee EJ, Kim HR, et al. p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res. 2003;63:5454–61.PubMed
36.
Sauer LA, Dauchy RT, Blask DE. Polyunsaturated fatty acids, melatonin, and cancer prevention. Biochem Pharmacol. 2001;61:1455–62.PubMedCrossRef
37.
Blask DE, Dauchy RT, Sauer LA et al. Oral melatonin supplementation in rats and a human subject suppresses the growth activity of steroid receptor negative human breast cancer xenografts in female nude rats via an MT1 receptor-mediated suppression of signal tranduction and linoleic acid uptake and metabolism. In: AACR Meeting Abstracts; 2005. pp. 1358.
38.
Reyes N, Reyes I, Tiwari R, et al. Effect of linoleic acid on proliferation and gene expression in the breast cancer cell line T47D. Cancer Lett. 2004;209:25–35.PubMedCrossRef
39.
Blask DE, Sauer LA, Dauchy RT, et al. Melatonin inhibition of cancer growth in vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transduction events. Cancer Res. 1999;59:4693–701.PubMed
40.
Wu J, Dauchy RT, Tirrell PC, et al. Light at night activates IGF-R/PDK signaling and accelerates tumor growth in human breast cancer xenografts. Cancer Res. 2011;71:2622–31.PubMedCrossRef
41.
Stevens RG. Electric power use and breast cancer: a hypothesis. Am J Epidemiol. 1987;125:556–61.PubMed
42.
Stevens R, London SJ. Breast cancer. In: Stevens RG, Wilson BW, Anderson LE, editors. The melatonin hypothesis: breast cancer and the use of electric power. Columbus: Battelle Press; 1997. p. 9–24.
43.
Stevens RG, Rea MS. Light in the built environment: potential role of circadian disruption in endocrine disruption and breast cancer. Cancer Causes Control. 2001;12:279–87.PubMedCrossRef
44.
Stevens RG. Light-at-night, circadian disruption and breast cancer: assessment of existing evidence. Int J Epidemiol. 2009;38:963–70.PubMedCrossRef
45.
Hansen J. Increased breast cancer risk among women who work predominantly at night. Epidemiology. 2001;12:74–7.PubMedCrossRef
46.
Davis S, Mirick DK, Stevens RG. Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst. 2001;93:1557–62.PubMedCrossRef
47.
Schernhammer ES, Laden F, Speizer FE, et al. Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J Natl Cancer Inst. 2001;93:1563–8.PubMedCrossRef
48.
Straif K, Baan R, Grosse Y, et al. Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol. 2007;8:1065–6.PubMedCrossRef
49.
Schernhammer ES, Hankinson SE. Urinary melatonin levels and breast cancer risk. J Natl Cancer Inst. 2005;97:1084–7.PubMedCrossRef
50.
Kloog I, Stevens RG, Haim A et al. Nighttime light level co-distributes with breast cancer incidence worldwide. Cancer Causes Control. 2010;21(12):2059–68.
51.
Schernhammer ES, Berrino F, Krogh V, et al. Urinary 6-sulfatoxymelatonin levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2008;100:898–905.PubMedCrossRef
52.
Dauchy RT, Sauer LA, Blask DE, et al. Light contamination during the dark phase in “photoperiodically controlled” animal rooms: effect on tumor growth and metabolism in rats. Lab Anim Sci. 1997;47:511–8.PubMed
53.
Dauchy RT, Blask DE, Sauer LA, et al. Dim light during darkness stimulates tumor progression by enhancing tumor fatty acid uptake and metabolism. Cancer Lett. 1999;144:131–6.PubMedCrossRef
54.
Cailotto C, Lei J, Van Der Vliet J, et al. Effects of nocturnal light on (clock) gene expression in peripheral organs: a role for the autonomic innervation of the liver. PLoS One. 2009;4:e5650.PubMedCrossRef
55.
Kennaway DJ, Owens JA, Voultsios A, et al. Metabolic homeostasis in mice with disrupted Clock gene expression in peripheral tissues. Am J Physiol Regul Integr Comp Physiol. 2007;293:R1528–37.PubMedCrossRef
56.
Guillaumond F, Dardente H, Giguere V, et al. Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J Biol Rhythms. 2005;20:391–403.PubMedCrossRef
57.
Xiang S, Coffelt SB, Mao L, et al. Period-2: a tumor suppressor gene in breast cancer. J Circadian Rhythms. 2008;6:4–12.PubMedCrossRef
58.
Yang X, Wood PA, Du-Quiton J, Ansell CM, Hrushesky WJ. Down reguation of circadian clock gene Period 2 accelerates breast cancer growth by alteringit daily growth rhythm. Breast Cancer Res Treat. 2009;117:423–31.PubMedCrossRef
59.
Kim E, Yoo Y, Yang W, Lim Y, Na T, Lee I, et al. Transcriptiohnal activation of Hif1 by RORα and its role in hypoxia signaling. Arterioscler Thromb Vasc Biol. 2008;28:1796–802.PubMedCrossRef
60.
Xiang S, Mao L, Yuan L, Hill SM. Effect of melatonin on the clock genes in breast epithelial and breast cancer cells. 100th Annual Mtg. American Association for Cancer Research, Denver, CO., Abst. #3596; 2009.
61.
Fu L, Pelicano H, Liu J, et al. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell. 2002;111:41–50.PubMedCrossRef
62.
Nakahata Y, Kaluzova M, Grimaldi B, et al. The NAD+ −dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell. 2008;134:329–40.PubMedCrossRef
63.
Liu T, Liu PY, Marshall GM. The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res. 2009;69:1702–5.PubMedCrossRef
64.
Hardeland R, Reiter RJ, Poeggeler B, et al. The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. Neurosci Biobehav Rev. 1993;17:347–57.PubMedCrossRef
65.
Poeggeler B, Thuermann S, Dose A, et al. Melatonin’s unique radical scavenging properties – roles of its functional substituents as revealed by a comparison with its structural analogs. J Pineal Res. 2002;33:20–30.PubMedCrossRef
66.
Matuszak Z, Rezka K, Chignell CF. Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. Free Rad Biol Med. 1997;23:367–72.PubMedCrossRef
67.
Stasica P, Ulanski P, Rosiak JM. Melatonin as a hydroxyl radical scavenger. J Pineal Res. 1998;25:65–6.PubMedCrossRef
68.
69.
Zhang H, Akbar M, Kim HY. Melatonin: an endogenous negative modulator of 12-lipoxygenatyion in the rat pineal gland. Biochem J. 1999;344:487–93.PubMedCrossRef
70.
Hardeland R. Melatonin: multiple functions in signaling and protection. In: Altmeyer P, Hoffman K, Stucker M, editors. Skin Cancer and UV Radiation. Berlin-Heidelberg: Springer; 1997. p. 186–98.
71.
Genova ML, Pich MM, Bernacchia A, et al. The mitochondrial production of reactive oxygen species in relation to aging and pathology. Ann NY Acad Sci. 2004;1011:86–100.PubMedCrossRef
Metadata
Title
Melatonin and Associated Signaling Pathways that Control Normal Breast Epithelium and Breast Cancer
Authors
Steven M. Hill
David E. Blask
Shulin Xiang
Lin Yuan
Lulu Mao
Robert T. Dauchy
Erin M. Dauchy
Tripp Frasch
Tamika Duplesis
Publication date
01-09-2011
Publisher
Springer US
Published in
Journal of Mammary Gland Biology and Neoplasia / Issue 3/2011
Print ISSN: 1083-3021
Electronic ISSN: 1573-7039
DOI
https://doi.org/10.1007/s10911-011-9222-4

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