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01.01.2015 | Original paper

Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects

verfasst von: Sarah J. Nyante, Marilie D. Gammon, Jay S. Kaufman, Jeannette T. Bensen, Dan Yu Lin, Jill S. Barnholtz-Sloan, Yijuan Hu, Qianchuan He, Jingchun Luo, Robert C. Millikan

Erschienen in: Cancer Causes & Control | Ausgabe 1/2015

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Abstract

Purpose

To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case–control study in North Carolina.

Methods

Cases (n = 1,972) were women 20–74 years old and diagnosed with breast cancer between 1993 and 2001. Population-based controls (n = 1,776) were frequency matched to cases by age and race. A total of 195 SNPs were genotyped, and linkage disequilibrium was evaluated using the r ² statistic. Odds ratios (ORs) and 95 % confidence intervals (CIs) for associations with breast cancer overall and by molecular subtype were estimated using logistic regression. Monte Carlo methods were used to control for multiple comparisons; two-sided p values <3.3 × 10⁻⁴ were statistically significant. Heterogeneity tests comparing the two most common subtypes, luminal A (n = 679) and basal-like (n = 200), were based on the Wald statistic.

Results

ESR1 rs6914211 (AA vs. AT+TT, OR 2.24, 95 % CI 1.51–3.33), ESR1 rs985191 (CC vs. AA, OR 2.11, 95 % CI 1.43–3.13), and PGR rs1824128 (TT+GT vs. GG, OR 1.33, 95 % CI 1.14–1.55) were associated with risk after accounting for multiple comparisons. Rs6914211 and rs985191 were in strong linkage disequilibrium among controls (African-Americans r ² = 0.70; whites r ² = 0.95). There was no evidence of heterogeneity between luminal A and basal-like subtypes, and the three SNPs were also associated with elevated risk of the less common luminal B, HER2+/ER−, and unclassified subtypes.

Conclusions

ESR1 and PGR SNPs were associated with risk, but lack of heterogeneity between subtypes suggests variants in hormone-related genes may play similar roles in the etiology of breast cancer molecular subtypes.

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Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRef

Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874PubMedCentralPubMedCrossRef

Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423PubMedCentralPubMedCrossRef

Millikan RC, Newman B, Tse CK, Moorman PG, Conway K, Dressler LG, Smith LV, Labbok MH, Geradts J, Bensen JT, Jackson S, Nyante S, Livasy C, Carey L, Earp HS, Perou CM (2008) Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 109:123–139PubMedCentralPubMedCrossRef

Yang XR, Sherman ME, Rimm DL, Lissowska J, Brinton LA, Peplonska B, Hewitt SM, Anderson WF, Szeszenia-Dabrowska N, Bardin-Mikolajczak A, Zatonski W, Cartun R, Mandich D, Rymkiewicz G, Ligaj M, Lukaszek S, Kordek R, Garcia-Closas M (2007) Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 16:439–443PubMedCrossRef

O’Brien KM, Cole SR, Tse CK, Perou CM, Carey LA, Foulkes WD, Dressler LG, Geradts J, Millikan RC (2010) Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study. Clin Cancer Res 16:6100–6110. doi:10.1158/1078-0432.CCR-10-1533 PubMedCentralPubMedCrossRef

Easton D (2012) Germline polymorphisms and susceptibility to breast cancer. San Antonio Breast Cancer Symposium, San Antonio, TX

Peng S, Lu B, Ruan W, Zhu Y, Sheng H, Lai M (2011) Genetic polymorphisms and breast cancer risk: evidence from meta-analyses, pooled analyses, and genome-wide association studies. Breast Cancer Res Treat 127:309–324. doi:10.1007/s10549-011-1459-5 PubMedCrossRef

Broeks A, Schmidt MK, Sherman ME et al (2011) Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20:3289–3303. doi:10.1093/hmg/ddr228 PubMedCentralPubMedCrossRef

10.

O’Brien KM, Cole SR, Engel LS, Bensen JT, Poole CL, Herring AH, Millikan RC (2013) Breast cancer subtypes and previously established genetic risk factors: A Bayesian approach. Cancer Epidemiol Biomarkers Prev. doi:10.1158/1055-9965.epi-13-0463 PubMed

11.

Barbieri RL (2004) The Breast. In: Strauss JF, Barbieri RL (eds) Yen and Jaffe’s reproductive endocrinology, 5th edn. Elsevier, Philadelphia, pp 307–326

12.

Conneely OM, Mulac-Jericevic B, Lydon JP (2003) Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms. Steroids 68:771–778PubMedCrossRef

13.

Gruber CJ, Tschugguel W, Schneeberger C, Huber JC (2002) Production and actions of estrogens. N Engl J Med 346:340–352PubMedCrossRef

14.

Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS (2003) Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 144:4562–4574PubMedCrossRef

15.

Ballare C, Uhrig M, Bechtold T, Sancho E, Di Domenico M, Migliaccio A, Auricchio F, Beato M (2003) Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells. Mol Cell Biol 23:1994–2008PubMedCentralPubMedCrossRef

16.

Ballare C, Vallejo G, Vicent GP, Saragueta P, Beato M (2006) Progesterone signaling in breast and endometrium. J Steroid Biochem Mol Biol 102:2–10PubMedCrossRef

17.

Payne AH, Hales DB (2004) Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev 25:947–970PubMedCrossRef

18.

Luu-The V (2001) Analysis and characteristics of multiple types of human 17beta-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol 76:143–151PubMedCrossRef

19.

Catalano MG, Frairia R, Boccuzzi G, Fortunati N (2005) Sex hormone-binding globulin antagonizes the anti-apoptotic effect of estradiol in breast cancer cells. Mol Cell Endocrinol 230:31–37PubMedCrossRef

20.

Fortunati N, Fissore F, Fazzari A, Becchis M, Comba A, Catalano MG, Berta L, Frairia R (1996) Sex steroid binding protein exerts a negative control on estradiol action in MCF-7 cells (human breast cancer) through cyclic adenosine 3′,5′-monophosphate and protein kinase A. Endocrinology 137:686–692PubMed

21.

Duax WL, Thomas J, Pletnev V, Addlagatta A, Huether R, Habegger L, Weeks CM (2005) Determining structure and function of steroid dehydrogenase enzymes by sequence analysis, homology modeling, and rational mutational analysis. Ann N Y Acad Sci 1061:135–148PubMedCentralPubMedCrossRef

22.

Millikan R, Eaton A, Worley K, Biscocho L, Hodgson E, Huang WY, Geradts J, Iacocca M, Cowan D, Conway K, Dressler L (2003) HER2 codon 655 polymorphism and risk of breast cancer in African Americans and whites. Breast Cancer Res Treat 79:355–364PubMedCrossRef

23.

Newman B, Moorman PG, Millikan R, Qaqish BF, Geradts J, Aldrich TE, Liu ET (1995) The Carolina Breast Cancer Study: integrating population-based epidemiology and molecular biology. Breast Cancer Res Treat 35:51–60PubMedCrossRef

24.

Weinberg CR, Sandler DP (1991) Randomized recruitment in case–control studies. Am J Epidemiol 134:421–432PubMed

25.

Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295:2492–2502PubMedCrossRef

26.

Huang WY, Newman B, Millikan RC, Schell MJ, Hulka BS, Moorman PG (2000) Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status. Am J Epidemiol 151:703–714PubMedCrossRef

27.

Livasy CA, Perou CM, Karaca G, Cowan DW, Maia D, Jackson S, Tse CK, Nyante S, Millikan RC (2007) Identification of a basal-like subtype of breast ductal carcinoma in situ. Hum Pathol 38:197–204PubMedCrossRef

28.

Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374PubMedCrossRef

29.

Frazer KA, Ballinger DG, Cox DR et al (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861PubMedCrossRef

30.

Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRef

31.

Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74:106–120PubMedCentralPubMedCrossRef

32.

de Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ, Altshuler D (2005) Efficiency and power in genetic association studies. Nat Genet 37:1217–1223PubMedCrossRef

33.

Haiman CA, Dossus L, Setiawan VW et al (2007) Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women. Cancer Res 67:1893–1897PubMedCrossRef

34.

Haiman CA, Stram DO, Pike MC, Kolonel LN, Burtt NP, Altshuler D, Hirschhorn J, Henderson BE (2003) A comprehensive haplotype analysis of CYP19 and breast cancer risk: the multiethnic cohort. Hum Mol Genet 12:2679–2692PubMedCrossRef

35.

Nyante SJ, Gammon MD, Kaufman JS, Bensen JT, Lin DY, Barnholtz-Sloan JS, Hu Y, He Q, Luo J, Millikan RC (2011) Common genetic variation in adiponectin, leptin, and leptin receptor and association with breast cancer subtypes. Breast Cancer Res Treat 129:593–606. doi:10.1007/s10549-011-1517-z PubMedCentralPubMedCrossRef

36.

Wigginton JE, Cutler DJ, Abecasis GR (2005) A note on exact tests of Hardy–Weinberg equilibrium. Am J Hum Genet 76:887–893PubMedCentralPubMedCrossRef

37.

Tian C, Hinds DA, Shigeta R, Kittles R, Ballinger DG, Seldin MF (2006) A genomewide single-nucleotide-polymorphism panel with high ancestry information for African American admixture mapping. Am J Hum Genet 79:640–649PubMedCentralPubMedCrossRef

38.

Barnholtz-Sloan JS, Chakraborty R, Sellers TA, Schwartz AG (2005) Examining population stratification via individual ancestry estimates versus self-reported race. Cancer Epidemiol Biomark Prev 14:1545–1551CrossRef

39.

Barnholtz-Sloan JS, McEvoy B, Shriver MD, Rebbeck TR (2008) Ancestry estimation and correction for population stratification in molecular epidemiologic association studies. Cancer Epidemiol Biomark Prev 17:471–477CrossRef

40.

Lin DY (2005) An efficient Monte Carlo approach to assessing statistical significance in genomic studies. Bioinformatics 21:781–787. doi:10.1093/bioinformatics/bti053 PubMedCrossRef

41.

Weinberg CR, Wacholder S (1990) The design and analysis of case–control studies with biased sampling. Biometrics 46:963–975PubMedCrossRef

42.

Stacey SN, Manolescu A, Sulem P et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39:865–869PubMedCrossRef

43.

Garcia-Closas M, Hall P, Nevanlinna H et al (2008) Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 4:e1000054PubMedCentralPubMedCrossRef

44.

Palmer JR, Ruiz-Narvaez EA, Rotimi CN, Cupples LA, Cozier YC, Adams-Campbell LL, Rosenberg L (2013) Genetic susceptibility loci for subtypes of breast cancer in an African American population. Cancer Epidemiol Biomarkers Prev 22:127–134. doi:10.1158/1055-9965.epi-12-0769 PubMedCentralPubMedCrossRef

45.

Stacey SN, Manolescu A, Sulem P et al (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40:703–706PubMedCrossRef

46.

Siddiq A, Couch FJ, Chen GK et al (2012) A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. Hum Mol Genet 21:5373–5384. doi:10.1093/hmg/dds381 PubMedCentralPubMedCrossRef

47.

Figueroa JD, Garcia-Closas M, Humphreys M et al (2011) Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20:4693–4706. doi:10.1093/hmg/ddr368 PubMedCentralPubMedCrossRef

48.

Stevens KN, Fredericksen Z, Vachon CM et al (2012) 19p13.1 is a triple-negative-specific breast cancer susceptibility locus. Cancer Res 72:1795–1803. doi:10.1158/0008-5472.can-11-3364 PubMedCentralPubMedCrossRef

49.

Stevens KN, Vachon CM, Lee AM et al (2011) Common breast cancer susceptibility loci are associated with triple-negative breast cancer. Cancer Res 71:6240–6249. doi:10.1158/0008-5472.can-11-1266 PubMedCentralPubMedCrossRef

50.

Nordgard SH, Johansen FE, Alnaes GI, Naume B, Borresen-Dale AL, Kristensen VN (2007) Genes harbouring susceptibility SNPs are differentially expressed in the breast cancer subtypes. Breast Cancer Res 9:113PubMedCentralPubMedCrossRef

51.

Dunning AM, Healey CS, Baynes C et al (2009) Association of ESR1 gene tagging SNPs with breast cancer risk. Hum Mol Genet 18:1131–1139PubMedCentralPubMedCrossRef

52.

Mavaddat N, Dunning AM, Ponder BA, Easton DF, Pharoah PD (2009) Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer. Cancer Epidemiol Biomark Prev 18:255–259CrossRef

53.

Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, Wen W, Levy S, Deming SL, Haines JL, Gu K, Fair AM, Cai Q, Lu W, Shu XO (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41:324–328PubMedCentralPubMedCrossRef

54.

Turnbull C, Ahmed S, Morrison J et al (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42:504–507. doi:10.1038/ng.586 PubMedCentralPubMedCrossRef

55.

Dunbier AK, Anderson H, Ghazoui Z, Lopez-Knowles E, Pancholi S, Ribas R, Drury S, Sidhu K, Leary A, Martin LA, Dowsett M (2011) ESR1 is co-expressed with closely adjacent uncharacterised genes spanning a breast cancer susceptibility locus at 6q25.1. PLoS Genet 7:e1001382. doi:10.1371/journal.pgen.1001382 PubMedCentralPubMedCrossRef

56.

Yu KD, Chen AX, Shao ZM (2010) No association between a progesterone receptor gene promoter polymorphism (+331G>A) and breast cancer risk in Caucasian women: evidence from a literature-based meta-analysis. Breast Cancer Res Treat 122:853–858. doi:10.1007/s10549-010-0738-x PubMedCrossRef

57.

Kagawa N, Hori H, Waterman MR, Yoshioka S (2004) Characterization of stable human aromatase expressed in E. coli. Steroids 69:235–243PubMedCrossRef

58.

Ma CX, Adjei AA, Salavaggione OE, Coronel J, Pelleymounter L, Wang L, Eckloff BW, Schaid D, Wieben ED, Adjei AA, Weinshilboum RM (2005) Human aromatase: gene resequencing and functional genomics. Cancer Res 65:11071–11082PubMedCrossRef

59.

Watanabe J, Harada N, Suemasu K, Higashi Y, Gotoh O, Kawajiri K (1997) Arginine–cysteine polymorphism at codon 264 of the human CYP19 gene does not affect aromatase activity. Pharmacogenetics 7:419–424PubMedCrossRef

60.

Lee KM, Abel J, Ko Y, Harth V, Park WY, Seo JS, Yoo KY, Choi JY, Shin A, Ahn SH, Noh DY, Hirvonen A, Kang D (2003) Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women. Br J Cancer 88:675–678PubMedCentralPubMedCrossRef

61.

Miyoshi Y, Iwao K, Ikeda N, Egawa C, Noguchi S (2000) Breast cancer risk associated with polymorphism in CYP19 in Japanese women. Int J Cancer 89:325–328PubMedCrossRef

62.

Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229PubMedCrossRef

63.

Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES (2001) Linkage disequilibrium in the human genome. Nature 411:199–204PubMedCrossRef

Titel: Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects
verfasst von: Sarah J. Nyante
Marilie D. Gammon
Jay S. Kaufman
Jeannette T. Bensen
Dan Yu Lin
Jill S. Barnholtz-Sloan
Yijuan Hu
Qianchuan He
Jingchun Luo
Robert C. Millikan
Publikationsdatum: 01.01.2015
Verlag: Springer International Publishing
Erschienen in: Cancer Causes & Control / Ausgabe 1/2015
Print ISSN: 0957-5243
Elektronische ISSN: 1573-7225
DOI: https://doi.org/10.1007/s10552-014-0491-2

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Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects