title: Elevated GH/IGF-I promotes mammary tumors in high-fat, but not low-fat, fed mice.
abstract: Growth hormone (GH) and/or insulin-like growth factor I (IGF-I) are thought to promote breast cancer based on reports showing circulating IGF-I levels correlate, in epidemiological studies, with breast cancer risk. Also, mouse models with developmental GH/IGF-I deficiency/resistance are less susceptible to genetic- or chemical-induced mammary tumorigenesis. However, given the metabolic properties of GH, medical strategies have been considered to raise GH to improve body composition and metabolic function in elderly and obese patients. Since hyperlipidemia, inflammation, insulin resistance and obesity increase breast cancer risk, elevating GH may serve to exacerbate cancer progression. To better understand the role GH/IGF-I plays in tumor formation, this study used unique mouse models to determine if reducing GH/IGF-I in adults protects against 7,12-dimethylbenz[α]anthracene (DMBA)-induced mammary tumor development, and if moderate elevations in endogenous GH/IGF-I alter DMBA-induced tumorigenesis in mice fed a standard-chow diet or in mice with altered metabolic function due to high-fat feeding. We observed that adult-onset isolated GH-deficient mice, which also have reduced IGF-I levels, were less susceptible to DMBA-treatment. Specifically, fewer adult-onset isolated GH-deficient mice developed mammary tumors compared with GH-replete controls. In contrast, chow-fed mice with elevated endogenous GH/IGF-I (HiGH mice) were not more susceptible to DMBA-treatment. However, high-fat-fed, HiGH mice showed reduced tumor latency and increased tumor incidence compared with diet-matched controls. These results further support a role of GH/IGF-I in regulating mammary tumorigenesis but suggest the ultimate consequences of GH/IGF-I on breast tumor development are dependent on the diet and/or metabolic status.
authors.affiliation: Research and Development Division, Jesse Brown Veteran Affairs Medical Center, 820 S. Damen Ave, Bldg. 11A, Suite 6215, MP151, Chicago, IL 60612, USA, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA, Lipid and Atherosclerosis Research Unit, University of Cordoba, Reina Sofia University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Cordoba, Spain, Department of Cell Biology, Physiology and Immunology, University of Cordoba, Reina Sofia University Hospital, IMIBIC and CIBERObn, Córdoba, Spain.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.affiliation: Research and Development Division, Jesse Brown Veteran Affairs Medical Center, 820 S. Damen Ave, Bldg. 11A, Suite 6215, MP151, Chicago, IL 60612, USA, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: José
authors.initials: J
authors.lastname: Córdoba-Chacón
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA and.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Lantvit
authors.affiliation: Anatomical Pathology Service, Reina Sofia University Hospital, Cordoba, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Ortega-Salas
authors.affiliation: Anatomical Pathology Service, Reina Sofia University Hospital, Cordoba, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Sanchez-Sanchez
authors.affiliation: Lipid and Atherosclerosis Research Unit, University of Cordoba, Reina Sofia University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Cordoba, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Jiménez
authors.affiliation: Lipid and Atherosclerosis Research Unit, University of Cordoba, Reina Sofia University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Cordoba, Spain.
authors.forename: José
authors.initials: J
authors.lastname: López-Miranda
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA and.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Swanson
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Reina Sofia University Hospital, IMIBIC and CIBERObn, Córdoba, Spain.
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Reina Sofia University Hospital, IMIBIC and CIBERObn, Córdoba, Spain.
authors.forename: Raúl M
authors.initials: RM
authors.lastname: Luque
authors.affiliation: Research and Development Division, Jesse Brown Veteran Affairs Medical Center, 820 S. Damen Ave, Bldg. 11A, Suite 6215, MP151, Chicago, IL 60612, USA, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA, kineman@uic.edu.
authors.forename: Rhonda D
authors.initials: RD
authors.lastname: Kineman
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D013006:Growth Hormone / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics*; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000473:pathology
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
references.citation: Dev Biol. 2001 Jan 1;229(1):163-75
references.pmid: 11133161
references.citation: Carcinogenesis. 2007 Jan;28(1):143-50
references.pmid: 16916863
references.citation: Endocrinology. 2010 Dec;151(12):5751-61
references.pmid: 20926579
references.citation: Nutr Cancer. 2004;50(1):46-54
references.pmid: 15572297
references.citation: Endocrinology. 2007 Oct;148(10):4536-44
references.pmid: 17584969
references.citation: Nutr Cancer. 1996;25(2):161-72
references.pmid: 8710685
references.citation: Cancer. 1994 Aug 1;74(3 Suppl):1055-62
references.pmid: 8039139
references.citation: Curr Pharm Des. 2012;18(26):3831-52
references.pmid: 22632748
references.citation: Eur J Endocrinol. 2011 Apr;164(4):485-9
references.pmid: 21292919
references.citation: Epidemiology. 1998 Sep;9(5):570-3
references.pmid: 9730040
references.citation: J Nutr. 1991 Nov;121(11):1876-82
references.pmid: 1941195
references.citation: Am J Clin Nutr. 2008 Nov;88(5):1304-12
references.pmid: 18996867
references.citation: Br J Cancer. 2001 Aug 3;85(3):428-30
references.pmid: 11487276
references.citation: Carcinogenesis. 2002 Jun;23(6):977-82
references.pmid: 12082019
references.citation: PLoS One. 2011 Jan 19;6(1):e15767
references.pmid: 21283519
references.citation: Endocrinology. 2013 Sep;154(9):3219-27
references.pmid: 23782942
references.citation: Cancer Res. 1980 Feb;40(2):368-73
references.pmid: 6243251
references.citation: J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):153-64
references.pmid: 16111884
references.citation: Eur J Cancer. 1993;29A(4):492-7
references.pmid: 8435198
references.citation: Endocr Rev. 2012 Apr;33(2):155-86
references.pmid: 22368183
references.citation: J Natl Cancer Inst. 1999 Jun 2;91(11):967-9
references.pmid: 10359550
references.citation: Cancer Res. 2010 Jan 1;70(1):4-7
references.pmid: 20028864
references.citation: Growth Horm IGF Res. 2010 Feb;20(1):1-7
references.pmid: 19800274
references.citation: Toxicol Pathol. 2005;33(6):726-37
references.pmid: 16263698
references.citation: Br J Nutr. 2008 Nov;100(5):942-6
references.pmid: 18377685
references.citation: Endocrinology. 2013 Jan;154(1):263-9
references.pmid: 23150490
references.citation: Obes Rev. 2012 Dec;13(12):1083-95
references.pmid: 22937964
references.citation: Endocrinology. 2004 Jul;145(7):3106-10
references.pmid: 15059953
references.citation: Nat Rev Cancer. 2012 Feb 16;12(3):159-69
references.pmid: 22337149
references.citation: Trends Endocrinol Metab. 2011 May;22(5):171-8
references.pmid: 21420315
references.citation: J Clin Endocrinol Metab. 2009 Oct;94(10):3931-8
references.pmid: 19622619
references.citation: J Acad Nutr Diet. 2013 Feb;113(2):288-96
references.pmid: 23127511
references.citation: Int J Cancer. 1995 Jul 28;62(3):266-70
references.pmid: 7543079
references.citation: Dev Dyn. 2011 Feb;240(2):347-56
references.pmid: 21246651
references.citation: Hormones (Athens). 2008 Apr-Jun;7(2):133-9
references.pmid: 18477550
references.citation: BMC Cancer. 2011 Aug 25;11:377
references.pmid: 21867536
references.citation: Mol Cell Endocrinol. 2010 Mar 25;316(2):147-53
references.pmid: 19723558
references.citation: Int J Obes (Lond). 2010 Sep;34(9):1415-26
references.pmid: 20231845
references.citation: Sci Transl Med. 2011 Feb 16;3(70):70ra13
references.pmid: 21325617
references.citation: Carcinogenesis. 1981;2(12):1327-33
references.pmid: 6799218
references.citation: Endocrinology. 2011 Dec;152(12):4825-37
references.pmid: 21990313
references.citation: Nat Rev Endocrinol. 2011 Jan;7(1):11-24
references.pmid: 20956999
references.citation: Cancer Res. 1997 Sep 15;57(18):3979-88
references.pmid: 9307282
references.citation: Horm Metab Res. 1985 Aug;17(8):421-4
references.pmid: 4054832
references.citation: Carcinogenesis. 2012 Jun;33(6):1225-30
references.pmid: 22436612
references.citation: Cancer Res. 2003 Aug 1;63(15):4384-8
references.pmid: 12907608
references.citation: Nature. 2010 Nov 4;468(7320):103-7
references.pmid: 20881963
references.citation: Int J Cancer. 2000 Dec 1;88(5):828-32
references.pmid: 11072255
references.citation: J Clin Endocrinol Metab. 2012 Jun;97(6):E907-16
references.pmid: 22442272
references.citation: J Mammary Gland Biol Neoplasia. 2012 Dec;17(3-4):251-61
references.pmid: 23054135
references.citation: Endocr Rev. 2009 Feb;30(1):51-74
references.pmid: 19075184