title: Associations between genetic variants in the TGF-β signaling pathway and breast cancer risk among Hispanic and non-Hispanic white women.
abstract: The TGF-β signaling pathway has a significant role in breast cancer initiation and promotion by regulating various cellular processes. We evaluated whether genetic variation in eight genes (TGF-β1, TGF-β2, TGF-βR1, TGF-βR2, TGF-βR3, RUNX1, RUNX2, and RUNX3) is associated with breast cancer risk in women from the Breast Cancer Health Disparities Study. A total of 3,524 cases (1,431 non-Hispanic whites (NHW); 2,093 Hispanics/Native Americans(NA)) and 4,209 population-based controls (1,599 NHWs; 2,610 Hispanics/NAs) were included in analyses. Genotypes for 47 single nucleotide polymorphisms (SNPs) were determined. Additionally, 104 ancestral informative markers estimated proportion of NA ancestry. Associations with breast cancer risk overall, by menopausal status, NA ancestry, and estrogen receptor (ER)/progesterone receptor tumor phenotype were evaluated. After adjustment for multiple comparisons, two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG = 1.15 95 % CI 1.04-1.26) and TGF-β1 (rs4803455 ORCA/AA = 0.89 95 % CI 0.81-0.98). RUNX3 (rs906296) and TGF-βR2 (rs3773644) were associated with risk in pre-menopausal women (p adj = 0.002 and 0.02, respectively) and in those with intermediate to high NA ancestry (p adj = 0.04 and 0.01, respectively). Self-reported race was strongly correlated with NA ancestry (r = 0.86). There was a significant interaction between NA ancestry and RUNX1 (rs7279383, p adj = 0.04). Four RUNX SNPs were associated with increased risk of ER- tumors. Results provide evidence that genetic variation in TGF-β and RUNX genes are associated with breast cancer risk. This is the first report of significant associations between genetic variants in TGF-β and RUNX genes and breast cancer risk among women of NA ancestry.
authors.affiliation: Department of Epidemiology and Population Health, School of Public Health and Information Sciences, James Graham Brown Cancer Center, University of Louisville, 485 E. Gray St. Room, Louisville, KY, 40202, USA, srdenk01@louisville.edu.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Boone
authors.forename: Kathy B
authors.initials: KB
authors.lastname: Baumgartner
authors.forename: Richard N
authors.initials: RN
authors.lastname: Baumgartner
authors.forename: Avonne E
authors.initials: AE
authors.lastname: Connor
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pinkston
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hines
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Stern
authors.forename: Anna R
authors.initials: AR
authors.lastname: Giuliano
authors.forename: Gabriela
authors.initials: G
authors.lastname: Torres-Mejia
authors.forename: Guy N
authors.initials: GN
authors.lastname: Brock
authors.forename: Frank D
authors.initials: FD
authors.lastname: Groves
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kerber
authors.forename: Roger K
authors.initials: RK
authors.lastname: Wolff
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D012306:Risk; D015398:Signal Transduction; D015206:Southwestern United States / Q000453:epidemiology / Q000208:ethnology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016212:Transforming Growth Factor beta
references.citation: J Clin Oncol. 2004 Feb 15;22(4):756-8
references.pmid: 14966109
references.citation: Oncogene. 2004 May 24;23(24):4308-14
references.pmid: 15156187
references.citation: Cancer Cell. 2002 Apr;1(3):213-5
references.pmid: 12086855
references.citation: Carcinogenesis. 2011 Mar;32(3):318-26
references.pmid: 21088106
references.citation: Nat Genet. 2007 Mar;39(3):352-8
references.pmid: 17293864
references.citation: Cancer Epidemiol Biomarkers Prev. 2002 Feb;11(2):211-4
references.pmid: 11867510
references.citation: Carcinogenesis. 2010 Feb;31(2):175-83
references.pmid: 19955393
references.citation: Breast Cancer Res Treat. 2010 Nov;124(1):243-9
references.pmid: 20232138
references.citation: Cancer Res. 2006 Jul 1;66(13):6512-20
references.pmid: 16818622
references.citation: J Clin Invest. 2009 Jun;119(6):1571-82
references.pmid: 19451693
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4254-8
references.pmid: 7753792
references.citation: J Biol Chem. 2001 Nov 16;276(46):42908-14
references.pmid: 11555647
references.citation: Oncogene. 2004 May 24;23(24):4232-7
references.pmid: 15156178
references.citation: Mol Biol Rep. 2010 Oct;37(7):3227-32
references.pmid: 19882361
references.citation: Oncogene. 2004 May 24;23(24):4198-208
references.pmid: 15156173
references.citation: Am J Epidemiol. 1986 Jun;123(6):1101-17
references.pmid: 3706280
references.citation: J Clin Oncol. 2005 Mar 20;23(9):2078-93
references.pmid: 15774796
references.citation: Carcinogenesis. 2011 Aug;32(8):1107-21
references.pmid: 21464040
references.citation: Curr Opin Genet Dev. 2003 Feb;13(1):43-7
references.pmid: 12573434
references.citation: Cell. 2002 Apr 5;109(1):113-24
references.pmid: 11955451
references.citation: Cancer Epidemiol Biomarkers Prev. 2012 Jul;21(7):1176-84
references.pmid: 22539603
references.citation: Nat Genet. 2004 Aug;36(8):790-2
references.pmid: 15284845
references.citation: Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):41-58
references.pmid: 16310402
references.citation: Cell. 2003 Jun 13;113(6):685-700
references.pmid: 12809600
references.citation: Heredity (Edinb). 2005 Sep;95(3):221-7
references.pmid: 16077740
references.citation: Annu Rev Cell Biol. 1990;6:597-641
references.pmid: 2177343
references.citation: Genes Dev. 1995 Jan 15;9(2):204-17
references.pmid: 7851794
references.citation: Cell Tissue Res. 2012 Jan;347(1):73-84
references.pmid: 21845401
references.citation: Cancer Res. 2003 May 15;63(10):2610-5
references.pmid: 12750287
references.citation: PLoS One. 2012;7(8):e42899
references.pmid: 22905183
references.citation: Cell. 2008 Jul 25;134(2):215-30
references.pmid: 18662538
references.citation: Endocr Relat Cancer. 2005 Dec;12(4):749-60
references.pmid: 16322320
references.citation: Am J Hum Genet. 2004 Apr;74(4):765-9
references.pmid: 14997420
references.citation: Source Code Biol Med. 2008 Dec 16;3:17
references.pmid: 19087314
references.citation: J Exp Clin Cancer Res. 2010 May 25;29:57
references.pmid: 20500843
references.citation: Oncogene. 2012 Jan 26;31(4):527-34
references.pmid: 21706051
references.citation: Cancer Res. 2005 Apr 15;65(8):3454-61
references.pmid: 15833881
references.citation: Breast Cancer Res Treat. 2010 Jan;119(2):437-42
references.pmid: 19390964
references.citation: Hum Genet. 2004 Feb;114(3):263-71
references.pmid: 14628215
references.citation: Breast Cancer. 2003;10(1):63-9
references.pmid: 12525765
references.citation: Genetics. 2000 Jun;155(2):945-59
references.pmid: 10835412
references.citation: Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1112-9
references.pmid: 21527583
references.citation: BMC Cancer. 2007 Sep 11;7:175
references.pmid: 17848193
references.citation: J Natl Cancer Inst. 1999 Dec 15;91(24):2096-101
references.pmid: 10601380
references.citation: Breast Cancer Res Treat. 2010 Jul;122(1):273-9
references.pmid: 20309626
references.citation: Oncogene. 2013 Apr 25;32(17):2121-30
references.pmid: 23045283
references.citation: Breast Cancer Res Treat. 2010 Nov;124(2):481-5
references.pmid: 20361250
references.citation: Carcinogenesis. 2012 Aug;33(8):1512-21
references.pmid: 22562547
references.citation: J Biol Chem. 2010 May 7;285(19):14747-55
references.pmid: 20207742
references.citation: Nat Rev Cancer. 2005 May;5(5):376-87
references.pmid: 15864279
references.citation: J Mammary Gland Biol Neoplasia. 2011 Jun;16(2):109-15
references.pmid: 21390570
references.citation: Int J Cancer. 2004 Oct 20;112(1):94-9
references.pmid: 15305380
references.citation: Immunol Lett. 2002 Jun 3;82(1-2):85-91
references.pmid: 12008039
references.citation: Cancer Epidemiol Biomarkers Prev. 2004 Mar;13(3):412-5
references.pmid: 15006917