title: Vitamin D mitigates the adverse effects of obesity on breast cancer in mice.
abstract: Obesity is an established risk factor for postmenopausal breast cancer (BCa), insulin resistance, and vitamin D deficiency, and all contribute to increased synthesis of mammary estrogens, the drivers of estrogen receptor-positive (ER+) BCa growth. As both dietary vitamin D and calcitriol treatments inhibit breast estrogen synthesis and signaling, we hypothesized that vitamin D would be especially beneficial in mitigating the adverse effects of obesity on ER+BCa. To assess whether obesity exerted adverse effects on BCa growth and whether vitamin D compounds could reduce these unfavorable effects, we employed a diet-induced obesity (DIO) model in ovariectomized C57BL/6 mice. Breast tumor cells originally from syngeneic Mmtv-Wnt1 transgenic mice were then implanted into the mammary fat pads of lean and obese mice. DIO accelerated the initiation and progression of the mammary tumors. Treatments with either calcitriol or dietary vitamin D reduced the adverse effects of obesity causing a delay in tumor appearance and inhibiting continued tumor growth. Beneficial actions of treatments with vitamin D or calcitriol on BCa and surrounding adipose tissue included repressed Esr1, aromatase, and Cox2 expression; decreased tumor-derived estrogen and PGE2; reduced expression of leptin receptors; and increased adiponectin receptors. We demonstrate that vitamin D treatments decreased insulin resistance, reduced leptin, and increased adiponectin signaling and also regulated the LKB1/AMPK pathway contributing to an overall decrease in local estrogen synthesis in the obese mice. We conclude that calcitriol and dietary vitamin D, acting by multiple interrelated pathways, mitigate obesity-enhanced BCa growth in a postmenopausal setting.
authors.affiliation: Department of Medicine-EndocrinologyStanford University School of Medicine, Stanford, CA, USA.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Swami
authors.affiliation: Department of Pediatrics-EndocrinologyStanford University School of Medicine, Stanford, CA, USA.
authors.forename: Aruna V
authors.initials: AV
authors.lastname: Krishnan
authors.affiliation: Department of Pediatrics-EndocrinologyStanford University School of Medicine, Stanford, CA, USA Cancer Biology ProgramStanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jasmaine
authors.initials: J
authors.lastname: Williams
authors.affiliation: Department of Pediatrics-EndocrinologyStanford University School of Medicine, Stanford, CA, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Department of Comparative MedicineStanford University School of Medicine, Stanford, CA, USA.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Albertelli
authors.affiliation: Heartland Assays IncAmes, IA, USA.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Horst
authors.affiliation: Department of Pediatrics-EndocrinologyStanford University School of Medicine, Stanford, CA, USA Cancer Biology ProgramStanford University School of Medicine, Stanford, CA, USA Institute for Stem Cell Biology and Regenerative MedicineStanford University School of Medicine, Stanford, CA, USA Stanford Cancer InstituteStanford University School of Medicine, Stanford, CA, USA dfeldman@stanford.edu feldman@stanford.edu.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Feldman
authors.affiliation: Department of Medicine-EndocrinologyStanford University School of Medicine, Stanford, CA, USA Stanford Cancer InstituteStanford University School of Medicine, Stanford, CA, USA dfeldman@stanford.edu feldman@stanford.edu.
authors.forename: David
authors.initials: D
authors.lastname: Feldman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000235:genetics; D002118:Calcium / Q000097:blood; D051546:Cyclooxygenase 2 / Q000235:genetics; D059305:Diet, High-Fat; D019587:Dietary Supplements; D015232:Dinoprostone / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D004970:Estrone / Q000378:metabolism; D005260:Female; D006801:Humans; D020738:Leptin / Q000097:blood; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D047368:Tumor Burden; D014807:Vitamin D / Q000097:blood / Q000494:pharmacology*
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D004967:Estrogens; D020738:Leptin; D012333:RNA, Messenger; D014807:Vitamin D; D004970:Estrone; D004958:Estradiol; D001141:Aromatase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D055372:AMP-Activated Protein Kinases; D015232:Dinoprostone; D002118:Calcium
keywords: adipokines; aromatase; breast cancer; obesity; vitamin D
references.citation: Obes Rev. 2009 Nov;10(6):660-70
references.pmid: 19460113
references.citation: Clin Cancer Res. 2013 Nov 15;19(22):6074-83
references.pmid: 23958744
references.citation: Nat Rev Immunol. 2011 Feb;11(2):85-97
references.pmid: 21252989
references.citation: J Clin Endocrinol Metab. 1993 Dec;77(6):1622-8
references.pmid: 8117355
references.citation: J Steroid Biochem Mol Biol. 2015 Apr;148:79-85
references.pmid: 25460302
references.citation: Nutr Cancer. 2008;60(4):534-41
references.pmid: 18584488
references.citation: Endocrinol Metab Clin North Am. 2014 Mar;43(1):205-32
references.pmid: 24582099
references.citation: Breast Cancer Res. 2015 Aug 19;17:112
references.pmid: 26286584
references.citation: Obesity (Silver Spring). 2014 Dec;22(12):2539-43
references.pmid: 25297931
references.citation: J Mol Endocrinol. 2013 Nov 26;51(3):T51-9
references.pmid: 24163427
references.citation: Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):925s-30s
references.pmid: 15701888
references.citation: Int J Cancer. 2007 Aug 1;121(3):514-9
references.pmid: 17397026
references.citation: Cancer Res. 2009 Jul 1;69(13):5392-9
references.pmid: 19509226
references.citation: J Clin Oncol. 2010 Sep 10;28(26):4058-65
references.pmid: 20697088
references.citation: Steroids. 2012 Sep;77(11):1107-12
references.pmid: 22801352
references.citation: Nat Rev Cancer. 2007 Sep;7(9):684-700
references.pmid: 17721433
references.citation: BMC Mol Biol. 2008 Jul 18;9:65
references.pmid: 18638371
references.citation: Breast Cancer Res Treat. 2010 Sep;123(2):591-6
references.pmid: 20300828
references.citation: Annu Rev Pharmacol Toxicol. 2011;51:311-36
references.pmid: 20936945
references.citation: Nat Rev Cancer. 2014 May;14 (5):342-57
references.pmid: 24705652
references.citation: Horm Cancer. 2011 Jun;2(3):190-202
references.pmid: 21686077
references.citation: Breast Cancer Res Treat. 1997 Jan;42(1):31-41
references.pmid: 9116316
references.citation: Clin Chem. 1996 Apr;42(4):586-92
references.pmid: 8605676
references.citation: Vitam Horm. 2013;93:1-49
references.pmid: 23810002
references.citation: Calcif Tissue Int. 1988 Oct;43(4):199-201
references.pmid: 3145124
references.citation: Cancer Metastasis Rev. 2010 Dec;29(4):641-53
references.pmid: 20821253
references.citation: Endocrinology. 2012 Jun;153(6):2576-87
references.pmid: 22454149
references.citation: Annu Rev Physiol. 2002;64:93-127
references.pmid: 11826265
references.citation: Endocr Relat Cancer. 2015 Dec;22(6):R365-86
references.pmid: 26373570
references.citation: Adv Exp Med Biol. 2014;810:33-51
references.pmid: 25207359
references.citation: J Steroid Biochem Mol Biol. 2015 Sep;153:35-44
references.pmid: 26209254
references.citation: Cancer Prev Res (Phila). 2015 Feb;8(2):120-8
references.pmid: 25468832
references.citation: Lancet. 2011 Aug 27;378(9793):815-25
references.pmid: 21872750
references.citation: Clin Chem. 1993 Mar;39(3):529-33
references.pmid: 8448871
references.citation: Mol Endocrinol. 2013 May;27(5):715-25
references.pmid: 23518927
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Annu Rev Med. 2013;64:45-57
references.pmid: 23121183
references.citation: Cancer Res. 2010 Jan 1;70(1):4-7
references.pmid: 20028864
references.citation: Endocr Relat Cancer. 2013 Jul 05;20(4):565-77
references.pmid: 23744764
references.citation: J Urol. 1999 Dec;162(6):2192-9
references.pmid: 10569618
references.citation: Annu Rev Med. 2015;66:297-309
references.pmid: 25587653
references.citation: Cancer Res. 2005 Sep 1;65(17):7917-25
references.pmid: 16140963
references.citation: Future Oncol. 2010 Mar;6(3):457-70
references.pmid: 20222801
references.citation: Arch Intern Med. 2007 Oct 22;167(19):2091-102
references.pmid: 17954804
references.citation: Endocrinology. 2010 Jan;151(1):32-42
references.pmid: 19906814
references.citation: Clin Cancer Res. 2000 Aug;6(8):3371-9
references.pmid: 10955825
references.citation: Arch Biochem Biophys. 2012 Jul 1;523(1):107-14
references.pmid: 22085499
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825