Skip to main content

Advertisement

SpringerLink
Log in

Role of cytochrome P450 genes in breast cancer etiology and treatment: effects on estrogen biosynthesis, metabolism, and response to endocrine therapy

  • Review article
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Purpose

The cytochrome P450 (CYP) genes are oxygenases involved in estrogen biosynthesis and metabolism, generation of DNA damaging procarcinogens, and response to anti-estrogen therapies. Since lifetime estrogen exposure is an established risk factor for breast cancer, determining the role of CYP genes in breast cancer etiology may provide critical information for understanding tumorigenesis and response to treatment.

Methods

This review summarizes literature available in PubMed published between 1993 and 2013 that focuses on studies evaluating the effects of DNA variants in CYP genes on estrogen synthesis, metabolism, and generation of procarcinogens in addition to response to anti-estrogen therapies.

Results

Evaluation of DNA variants in estrogen metabolism genes was largely inconclusive. Meta-analyses of data from CYP19A1 support an association between the number of (TTTA) n repeats in intron 4 and breast cancer risk, but the biological mechanism for this relationship is unknown. Associations between single nucleotide polymorphism in CYP1B1 and DNA damage caused by procarcinogenic estrogen metabolites were ambiguous. Variants in CYP2D6 are associated with altered metabolism tamoxifen; however, current data do not support widespread clinical testing. The effect of variants in CYP19A1 in response to aromatase inhibitors is also questionable.

Conclusion

Evaluation of DNA variants in CYP genes involved with estrogen metabolism or treatment response has been inconclusive, reflecting small samples sizes, tumor heterogeneity, and differences between populations. Better-powered studies that account for genetic backgrounds and tumor phenotypes are thus necessary.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Nebert DW, Russell DW (2002) Clinical importance of the cytochromes P450. Lancet 360(9340):1155–1162

    CAS  PubMed  Google Scholar 

  2. Daly AK (2004) Pharmacogenetics of the cytochromes P450. Curr Top Med Chem 4(16):1733–1744

    CAS  PubMed  Google Scholar 

  3. Aithal GP, Day CP, Kesteven PJ, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353(9154):717–719

    CAS  PubMed  Google Scholar 

  4. Marichalar-Mendia X, Rodrigurez-Tojo MJ, Acha-Sagredo A, Rey-Barja N, Aguirre-Urizar JM (2010) Oral cancer and polymorphisms of ethanol metabolising genes. Oral Oncol 46:9–13

    CAS  PubMed  Google Scholar 

  5. Kristiansen W, Haugen TB, Witczak O, Andersen JM, Fossa SD, Aschim EL (2011) CYP1A1, CYP3A5 and CYP3A7 polymorphisms and testicular cancer susceptibility. Int J Androl 34(1):77–83

    CAS  PubMed  Google Scholar 

  6. Pastina I, Giovannetti E, Chioni A et al (2010) Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in castration–resistant prostate cancer (CRPC) patients. BMC Cancer 10:511

    PubMed Central  PubMed  Google Scholar 

  7. Kaaks R, Berrino F, Key T et al (2005) Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 97(10):755–765

    CAS  PubMed  Google Scholar 

  8. Kaaks R, Rinaldi S, Key TJ et al (2005) Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12(4):1071–1082

    CAS  PubMed  Google Scholar 

  9. Key T, Appleby P, Barnes I, Reeves G, Endogenous Hormones and Breast Cancer Collaborative Group (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94(8):606–616

    Google Scholar 

  10. Hayashi SI, Eguchi H, Tanimoto K et al (2003) The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application. Endocr Relat Cancer 10(2):193–202

    CAS  PubMed  Google Scholar 

  11. Witt BR, Thorneycroft IH (1990) Reproductive steroid hormones: generation, degradation, reception and action. Clin Obstet Gynecol 33(3):563–575

    CAS  PubMed  Google Scholar 

  12. Tsuchiya Y, Nakajima M, Yokoi T (2005) Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett 227(2):115–124

    CAS  PubMed  Google Scholar 

  13. Le Marchand L, Donlon T, Kolonel LN, Henderson BE, Wilkens LR (2005) Estrogen metabolism-related genes and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomark Prev 14(8):1998–2003

    Google Scholar 

  14. Long JR, Egan KM, Dunning L et al (2006) Population-based case–control study of AhR (aryl hydrocarbon receptor) and CYP1A2 polymorphisms and breast cancer risk. Pharmacogenet Genomics 16(4):237–243

    CAS  PubMed  Google Scholar 

  15. Qiu LX, Yao L, Mao C et al (2010) Lack of association of CYP1A2-164 A/C polymorphism with breast cancer susceptibility: a meta-analysis involving 17,600 subjects. Breast Cancer Res Treat 122(2):521–525

    CAS  PubMed  Google Scholar 

  16. Sangrajrang S, Sato Y, Sakamoto H et al (2009) Genetic polymorphisms of estrogen metabolizing enzyme and breast cancer risk in Thai women. Int J Cancer 125(4):837–843

    CAS  PubMed  Google Scholar 

  17. Cribb AE, Joy Knight M, Guemsey J et al (2011) CYP17, catechol-o-methyltransferase, and glutathione transferase M1 genetic polymorphisms, lifestyle factors, and breast cancer risk in women on Prince Edward Island. Breast J 17(1):24–31

    PubMed  Google Scholar 

  18. Verla-Tebit E, Wang-Gohrke S, Chang-Claude J (2005) CYP17 5′-UTR MspA1 polymorphism and the risk of premenopausal breast cancer in a German population-based case–control study. Breast Cancer Res 7(4):R455–R464

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Bergman-Jungestrom M, Gentile M, Lundin AC, Wingren S (1999) Association between CYP17 gene polymorphism and risk of breast cancer in young women. Int J Cancer 84(4):350–353

    CAS  PubMed  Google Scholar 

  20. Feigelson HS, Coetzee GA, Kolonel LN, Ross RK, Henderson BE (1997) A polymorphism in the CYP17 gene increases the risk of breast cancer. Cancer Res 57(6):1063–1065

    CAS  PubMed  Google Scholar 

  21. Justenhoven C, Hamann U, Schubert F et al (2008) Breast cancer: a candidate gene approach across the estrogen metabolic pathway. Breast Cancer Res Treat 108(1):137–149

    CAS  PubMed  Google Scholar 

  22. Travis RC, Churchman M, Edwards SA et al (2012) No association of polymorphisms in CYP17, CYP19, and HSD17-B1 with plasma estradiol concentrations in 1,090 British women. Cancer Epidemiol Biomark Prev 13(12):2282–2284

    Google Scholar 

  23. Chang JH, Gertig DM, Chen X et al (2005) CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors: Australian Breast Cancer Family Study. Breast Cancer Res 7(4):R513–R521

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Einarsdottir K, Rylander-Rudqvist T, Humphreys K et al (2005) CYP17 gene polymorphism in relation to breast cancer risk: a case–control study. Breast Cancer Res 7(6):R890–R896

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Sliva SN, Cabral MN, Bezerra de Castro G et al (1998) Breast cancer risk and polymorphisms in genes involved in metabolism of estrogens (CYP17, HSD17beta1, COMT and MnSOD): possible protective role of MnSOD gene polymorphism Val/Ala and Ala/Ala in women that never breast fed. J Oncol Rep 16(4):781–788

    Google Scholar 

  26. Helzlsouer KJ, Huang H, Strickland PT et al (1998) Association between CYP17 polymorphisms and development of breast cancer. Cancer Epidemiol Biomark Prev 7:945–949

    CAS  Google Scholar 

  27. Agarwal VR, Bulun SE, Leitch M, Rohrich R, Simpson ER (1996) Use of alternative promoters to express the aromatase cytochrome P450 (CYP19) gene in breast adipose tissues of cancer-free and breast cancer patients. J Clin Endocrinol Metab 81(11):3843–3849

    CAS  PubMed  Google Scholar 

  28. Utsumi T, Harada N, Maruta M, Takagi Y (1996) Presence of alternatively spliced transcripts of aromatase gene in human breast cancer. J Clin Endocrinol Metab 81(6):2344–2349

    CAS  PubMed  Google Scholar 

  29. Singh S, Chakravarti D, Edney JA et al (2005) Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast carcinoma. Oncol Rep 14(4):1091–1096

    CAS  PubMed  Google Scholar 

  30. Salhab M, Reed MJ, Al Sarakbi W, Jiang WG, Mokbel K (2006) The role of aromatase and 17-beta-hydroxysteroid dehydrogenase type 1 mRNA expression in predicting the clinical outcome of human breast cancer. Breast Cancer Res Treat 99(2):155–162

    CAS  PubMed  Google Scholar 

  31. Okobia MN, Bunker CH, Zmuda JM et al (2006) Simple tandem repeat (TTTA)n polymorphism in CYP19 (aromatase) gene and breast cancer risk in Nigerian women. J Carcinog 5:12

    PubMed Central  PubMed  Google Scholar 

  32. Ribeiro FS, de Amorim LM, de Almeida Simao T, Mendonca GA, de Moura Gallo CV, Pinto LF (2006) CYP19 (TTTA)n polymorphism and breast cancer risk in Brazilian women. Toxicol Lett 164(1):90–95

    CAS  PubMed  Google Scholar 

  33. Han DF, Zhou X, Hu MB et al (2005) Polymorphisms of estrogen-metabolizing genes and breast cancer risk: a multigenic study. Chin Med J 118(18):1507–1516

    CAS  PubMed  Google Scholar 

  34. Baxter SW, Choong DY, Eccles DM, Campbell IG (2001) Polymorphic variation in CYP19 and the risk of breast cancer. Carcinogenesis 22(2):347–349

    CAS  PubMed  Google Scholar 

  35. 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(4):325–328

    CAS  PubMed  Google Scholar 

  36. Haiman CA, Hankinson SE, Spiegelman D et al (2000) A tetranucleotide repeat polymorphism in CYP19 and breast cancer risk. Int J Cancer 87(2):204–210

    CAS  PubMed  Google Scholar 

  37. Healey CS, Dunning AM, Durocher F et al (2000) Polymorphisms in the human aromatase cytochrome P450 gene (CYP19) and breast cancer risk. Carcinogenesis 21(2):189–193

    CAS  PubMed  Google Scholar 

  38. Probst-Hensch NM, Ingles SA, Diep AT et al (1999) Aromatase and breast cancer susceptibility. Endocr Relat Cancer 6(2):165–173

    CAS  PubMed  Google Scholar 

  39. Cai Q, Kataoka N, Li C et al (2008) Haplotype analyses of CYP19A1 gene variants and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomark Prev 17(1):27–32

    CAS  Google Scholar 

  40. Kim JY, Lee CS, Kim HO et al (2009) The association between genetic polymorphisms in CYP19 and breast cancer risk in Korean women. Oncol Rep 22(3):487–492

    CAS  PubMed  Google Scholar 

  41. Ma X, Qi X, Chen C et al (2010) Association between CYP19 polymorphisms and breast cancer risk: results from 10,592 cases and 11,720 controls. Breast Cancer Res Treat 122:2–495

    Google Scholar 

  42. Zhang B, Beeghly-Fadiel A, Long J, Zheng W (2011) Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol 12(5):477–488

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Olson JE, Ingle JN, Ma CX et al (2007) A comprehensive examination of CYP19 variation and risk of breast cancer using two haplotype tagging approaches. Breast Cancer Res Treat 102(2):237–247

    PubMed Central  PubMed  Google Scholar 

  44. Kristensen VN, Harada N, Yoshimura N et al (2000) Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene 1919:1329–1333

    Google Scholar 

  45. Zhang L, Gu L, Qian B et al (2009) Association of genetic polymorphisms of ER-alpha and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women. Breast Cancer Res Treat 114(2):327–338

    CAS  PubMed  Google Scholar 

  46. Zins K, Mogg M, Schneeberger C, Abraham D, Schreiber M (2014) Analysis of the rs10046 polymorphism of aromatase (CYP19) in premenopausal onset of human breast cancer. Int J Mol Sci 15(1):712–724

    PubMed Central  PubMed  Google Scholar 

  47. Chen C, Sakoda LC, Doherty JA et al (2008) Genetic variation in CYP19A1 and risk of breast cancer and fibrocystic breast conditions among women in Shanghai, China. Cancer Epidemiol Biomark Prev 17(12):3457–3466

    CAS  Google Scholar 

  48. Haiman CA, Hankinson SE, Spiegelman D, Brown M, Hunter DJ (2002) No association between a single nucleotide polymorphism in CYP19 and breast cancer risk. Cancer Epidemiol Biomark Prev 11:215–216

    CAS  Google Scholar 

  49. Dunning AM, Dowsett M, Healey CS et al (2004) Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 96(12):936–945

    CAS  PubMed  Google Scholar 

  50. 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(5):1893–1897

    CAS  PubMed  Google Scholar 

  51. Pineda B, Garcia-Perez MA, Cano A, Lluch A, Eroles P (2013) Associations between aromatase CYP19 rs10046 polymorphism and breast cancer risk: from a case–control to a meta-analysis of 20,098 subjects. PLoS One 8(1):e53902

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Ma CX, Adjei AA, Salavaggione OE et al (2005) Human aromatase: gene resequencing and functional genomics. Cancer Res 65(23):11071–11082

    CAS  PubMed  Google Scholar 

  53. Hirose K, Matsuo K, Toyama T, Iwata H, Hamajima N, Tajima K (2004) The CYP19 gene codon 19 Trp/Arg polymorphism increases breast cancer risk in subsets of premenopausal Japanese. Cancer Epidemiol Biomark Prev 13(8):1407–1411

    CAS  Google Scholar 

  54. Lee K-M, Abel J, Ko Y et al (2003) Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women. Br J Cancer 88:675–678

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Cavalieri E, Frenkel K, Liehr JG, Rogan E, Roy D (2000) Chapter 4: estrogens as endogenous genotoxic agents—DNA adducts and mutations. J Natl Cancer Inst Monogr 27:75–93

    CAS  PubMed  Google Scholar 

  56. Liehr JG (2000) Is estradiol a genotoxic mutagenic carcinogen? Endocr Rev 21(1):40–54

    CAS  PubMed  Google Scholar 

  57. Kong LY, Szaniszlo P, Albrecht T, Liehr JG (2012) Frequency and molecular analysis of hprt mutations induced by estradiol in Chinese hamster V79 cells. Int J Oncol 17(6):1141–1149

    Google Scholar 

  58. Fernandez SV, Russo IH, Russo J (2006) Estradiol and its metabolites 4-hydroxyestradiol and 2-hydroxyestradiol induce mutations in human breast epithelial cells. Int J Cancer 118(8):1862–1868

    CAS  PubMed  Google Scholar 

  59. Hontz AE, Li SA, Lingle WL et al (2007) Aurora A and B overexpression and centrosome amplification in early estrogen-induced tumor foci in the Syrian hamster kidney: implications for chromosomal instability, aneuploidy, and neoplasia. Cancer Res 67(7):2957–2963

    CAS  PubMed  Google Scholar 

  60. Li JJ, Weroha J, Lingle WL, Papa D, Salisbury JL, Li SA (2004) Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats. Proc Natl Acad Sci USA 191(52):18123–18128

    Google Scholar 

  61. Stopper H, Schmitt E, Gregor C, Mueller SO, Fischer WH (2003) Increased cell proliferation is associated with genomic instability: elevated micronuclei frequencies in estradiol-treated human ovarian cancer cells. Mutagenesis 18(3):243–247

    CAS  PubMed  Google Scholar 

  62. Cavalieri EL, Stack DE, Devanesan PD et al (1997) Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci USA 94(20):10937–10942

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Chakravarti D, Mailander PC, Li K-M et al (2001) Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene. Oncogene 20:7945–7953

    CAS  PubMed  Google Scholar 

  64. Demple B, Harrison L (1994) Repair of oxidative damage to DNA: enzymology and biology. Annu Rev Biochem 63:915–948

    CAS  PubMed  Google Scholar 

  65. Djuric Z, Heibrun LK, Simon MS et al (1996) Levels of 5-hydroxymethyl-2′-deoxyuridine in DNA from blood as a marker of breast cancer. Cancer 77(4):691–696

    CAS  PubMed  Google Scholar 

  66. Frenkel K, Karkoszka J, Glassman T et al (1998) Serum autoantibodies recognizing 5-hydroxymethyl-2′-deoxyuridine, an oxidized DNA base, as biomarkers of cancer risk in women. Cancer Epidemiol Biomark Prev 7(1):49–57

    CAS  Google Scholar 

  67. Poulsen HE (2005) Oxidative DNA modifications. Exp Toxicol Pathol 57(Suppl 1):161–169

    CAS  PubMed  Google Scholar 

  68. Malins DC, Polissar NL, Gunselman SJ (1996) Progression of human breast cancers to the metastatic state is linked to hydroxyl radical-induced DNA damage. Proc Natl Acad Sci USA 93(6):2557–2563

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Yoshie Y, Ohshima H (1998) Synergistic induction of DNA strand breakage by catechol-estrogen and nitric oxide: implications for hormonal carcinogenesis. Free Radic Biol Med 24(2):341–348

    CAS  PubMed  Google Scholar 

  70. Liehr JG, Fang WF, Sirbasku DA, Ari-Ulubelen A (1986) Carcinogenicity of catechol estrogens in Syrian hamsters. J Steroid Biochem 24(1):353–356

    CAS  PubMed  Google Scholar 

  71. Hanna IH, Dawling S, Roodi N, Guengerich FP, Parl FF (2000) Cytochrome P450 1B1 (CYP1B1) pharmacogenetics: association of polymorphisms with functional differences in estrogen hydroxylation activity. Cancer Res 60(13):3440–3444

    CAS  PubMed  Google Scholar 

  72. Bandiera S, Weidlich S, Harth V, Broede P, Ko Y, Friedberg T (2005) Proteasomal degradation of human CYP1B1: effect of the Asn453Ser polymorphism on the post-translational regulation of CYP1B1 expression. Mol Pharmacol 67(2):435–443

    CAS  PubMed  Google Scholar 

  73. Landi MT, Bergen AW, Baccarelli A et al (2005) CYP1A1 and CYP1B1 genotypes, haplotypes, and TCDD-induced gene expression in subjects from Seveso, Italy. Toxicology 207(2):191–202

    CAS  PubMed  Google Scholar 

  74. Matyjasik J, Cybulski C, Masojc B et al (2007) CYP1B1 and predisposition to breast cancer in Poland. Breast Cancer Res Treat 106(3):383–388

    PubMed  Google Scholar 

  75. Gaudet MM, Chanock S, Lissowska J et al (2006) Genetic variation of Cytochrome P450 1B1 (CYP1B1) and risk of breast cancer among Polish women. Pharmacogenet Genomics 16(8):547–553

    CAS  PubMed  Google Scholar 

  76. Delort L, Satih S, Kwiatkowski F, Bignon YJ, Bernard-Gallon DJ (2010) Evaluation of breast cancer risk in a multigenic model including low penetrance genes involved in xenobiotic and estrogen metabolisms. Nutr Cancer 62(2):243–251

    CAS  PubMed  Google Scholar 

  77. Zheng W, Xie DW, Jin F et al (2000) Genetic polymorphism of cytochrome P450-1B1 and risk of breast cancer. Cancer Epidemiol Biomark Prev 9(2):147–150

    CAS  Google Scholar 

  78. Bailey LR, Roodi N, Dupont WD, Parl FF (1998) Association of cytochrome P450 1B1 (CYP1B1) polymorphism with steroid receptor status in breast cancer. Cancer Res 58(22):5038–5041

    CAS  PubMed  Google Scholar 

  79. Paracchini V, Raimondi S, Gram IT et al (2007) Meta- and pooled analyses of the cytochrome P-450 1B1 Val432Leu polymorphism and breast cancer: a HuGE-GSEC review. Am J Epidemiol 165(2):115–125

    PubMed  Google Scholar 

  80. Wen W, Cai Q, Shu XO et al (2005) Cytochrome P450 1B1 and catechol-O-methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the shanghai breast cancer study and a meta-analysis. Cancer Epidemiol Biomark Prev 14(2):329–335

    CAS  Google Scholar 

  81. Yao L, Fang F, Wu Q, Zhong Y, Yu L (2010) No association between CYP1B1 Val432Leu polymorphism and breast cancer risk: a meta-analysis involving 40,303 subjects. Breast Cancer Res Treat 122(1):237–242

    CAS  PubMed  Google Scholar 

  82. Keen JC, Davidson NE (2003) The biology of breast carcinoma. Cancer 97(3 Suppl):825–833

    PubMed  Google Scholar 

  83. Elledge RM, Fuqua SA (2000) Estrogen and progesterone receptors. In: Harris JR (ed) Diseases of the breast, 2nd edn. Lippencott Williams and Wilkins, Philadelphia, pp 471–488

    Google Scholar 

  84. Kennecke H, Yerushalmi R, Woods R et al (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28(20):3271–3277

    PubMed  Google Scholar 

  85. Fisher B, Costantino JP, Wickerham DL et al (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90(18):1371–1388

    CAS  PubMed  Google Scholar 

  86. Higgins MJ, Stearns V (2010) CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep 12(1):7–15

    CAS  PubMed  Google Scholar 

  87. Ramon y Cajal T, Altes A, Pare L et al (2010) Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment. Breast Cancer Res Treat 119(1):33–38

    CAS  PubMed  Google Scholar 

  88. Schroth W, Antoniadou L, Fritz P et al (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25(33):5187–5193

    CAS  PubMed  Google Scholar 

  89. Bonanni B, Macis D, Maisonneuve P et al (2006) Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian tamoxifen trial. J Clin Oncol 24(22):3708–3709

    PubMed  Google Scholar 

  90. Wegman P, Vainikka L, Stal O et al (2005) Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7(3):R284–R290

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Goetz MP, Rae JM, Suman VJ et al (2005) Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23(36):9312–9318

    CAS  PubMed  Google Scholar 

  92. Lim HS, Ju Lee H, Seok Lee K, Sook Lee E, Jang IJ, Ro J (2007) Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25(25):3837–3845

    CAS  PubMed  Google Scholar 

  93. Kiyotani K, Mushiroda T, Sasa M et al (2008) Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci 99(5):995–999

    CAS  PubMed  Google Scholar 

  94. Hertz DL, McLeod HL, Irwin WJ (2012) Tamoxifen and CYP2D6: a contradiction of data. Oncologist 17(5):620–630

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Markkula A, Hjertberg M, Rose C, Ingvar C, Jernström H (2014) No association found between CYP2D6 genotype and early breast cancer events in tamoxifen-treated patients. Acta Oncol 53(2):195–200

    CAS  PubMed  Google Scholar 

  96. Nowell SA, Ahn J, Rae JM et al (2005) Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91(3):249–258

    CAS  PubMed  Google Scholar 

  97. Okishiro M, Taguchi T, Jin Kim S, Shimazu K, Tamaki Y, Noguchi S (2009) Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer 115(5):952–961

    CAS  PubMed  Google Scholar 

  98. Seruga B, Amir E (2010) Cytochrome P450 2D6 and outcomes of adjuvant tamoxifen therapy: results of a meta-analysis. Breast Cancer Res Treat 122(3):609–617

    CAS  PubMed  Google Scholar 

  99. Zeng Z, Liu Y, Liu Z et al (2013) CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients: a meta-analysis. Cancer Chemother Pharmacol 72(2):287–303

    CAS  PubMed  Google Scholar 

  100. Province MA, Goetz MP, Brauch H et al (2014) CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clin Pharmacol Ther 95(2):216–227

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Jung JA, Lim HS (2014) Association between CYP2D6 genotypes and the clinical outcomes of adjuvant tamoxifen for breast cancer: a meta-analysis. Pharmacogenomics 15(1):49–60

    CAS  PubMed  Google Scholar 

  102. Flockhart DA (2007) Drug interactions: cytochrome P450 drug interaction table

  103. Steams V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95(23):1758–1764

  104. Jin Y, Desta Z, Steams V et al (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97(1):30–39

    CAS  PubMed  Google Scholar 

  105. Kelly CM, Jurrlink DN, Gomes T et al (2010) Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 340:c693

    PubMed Central  PubMed  Google Scholar 

  106. Lash TL, Cronin-Fenton D, Ahern TP et al (2010) Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncol 49(3):305–312

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Holtzman D (2009) Tamoxifen, antidepressants, and CYP2D6: the conundrum continues. J Natl Cancer Inst 101(20):1370–1371

    Google Scholar 

  108. Binkhorst L, Mathijssen RH, van Herk-Sukel MP et al (2013) Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen. Breast Cancer Res Treat 139(3):923–929

    CAS  PubMed  Google Scholar 

  109. Jain KK (2005) Applications of AmpliChip CYP450. Mol Diagn 9(3):119–127

    PubMed  Google Scholar 

  110. Hartman AR, Helft P (2007) The ethics of CYP2D6 testing for patients considering tamoxifen. Breast Cancer Res 9(2):103

    PubMed Central  PubMed  Google Scholar 

  111. Hayes DF, Steams V, Rae J, Flockhart D, Consortium on Breast Cancer Pharmacogenomics (2008) A model citizen? Is tamoxifen more effective than aromatase inhibitors if we pick the right patients? J Natl Cancer Inst 100(9):610–613

    Google Scholar 

  112. Fleeman N, Martin Saborido C, Payne K et al (2011) The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review. Health Technol Assess 15(33):1–102

    Google Scholar 

  113. Regan MM, Leyland-Jones B, Bouzyk M et al (2012) CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1–98 trial. J Natl Cancer Inst 104(6):441–451

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Lum DW, Perel P, Hingorani AD, Holmes MV (2013) CYP2D6 genotype and tamoxifen response for breast cancer: a systematic review and meta-analysis. PLoS One 8(10):e76648

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Dowsett M (1999) Drug and hormone interactions of aromatase inhibitors. Endocr Relat Cancer 6(2):181–185

    CAS  PubMed  Google Scholar 

  116. Baum M, Budzar AU, Cuzick J et al (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359(9324):2131–2139

    CAS  PubMed  Google Scholar 

  117. Breast International Group (BIG) 1–98 Collaborative Group, Thurlimann B, Keshaviah A et al (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353(26):2747–2757

    Google Scholar 

  118. Coombes RC, Hall E, Gibson LJ et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350(11):1081–1092

    CAS  PubMed  Google Scholar 

  119. Amir E, Seruga B, Niraula S, Carlsson L, Ocana A (2011) Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst 103(17):1299–1309

    CAS  PubMed  Google Scholar 

  120. Colomer R, Monzo M, Tusquets I et al (2008) A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clin Cancer Res 14(3):811–816

    CAS  PubMed  Google Scholar 

  121. Garcia-Casado Z, Guerrero-Zotano A, Llombart-Cussac A et al (2010) A polymorphism at the 3′-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole. BMC Cancer 10:36

    PubMed Central  PubMed  Google Scholar 

  122. Wang L, Ellsworth KA, Moon I et al (2010) Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer Res 70(1):319–328

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Park IH, Lee YS, Lee KS et al (2011) Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer. Cancer Chemother Pharmacol 68(5):1263–1271

    CAS  PubMed  Google Scholar 

  124. Ferraldeschi R, Amedos M, Hadfield KD et al (2012) Polymorphisms of CYP19A1 and response to aromatase inhibitors in metastatic breast cancer patients. Breast Cancer Res Treat 133(3):1191–1198

    CAS  PubMed  Google Scholar 

  125. Bell DW, Brannigan BW, Matsuo K et al (2008) Increased prevalence of EGFR-mutant lung cancer in women and in East Asian populations: analysis of estrogen-related polymorphisms. Clin Cancer Res 14(13):4079–4084

    PubMed Central  CAS  PubMed  Google Scholar 

  126. Weyandt J, Ellsworth RE, Hooke JA, Shriver CD, Ellsworth DL (2008) Environmental chemicals and breast cancer risk—a structural chemistry perspective. Curr Med Chem 15(26):2680–2701

    CAS  PubMed  Google Scholar 

  127. Ahmed A, Shahabuddin S, Sheikh S et al (2010) Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects. Clin Pharmacol Ther 88(6):814–817

    Google Scholar 

Download references

Acknowledgments

This research was supported by a grant from the United States Department of Defense (Military Molecular Medicine Initiative MDA W81XWH-05-2-0075, Protocol 01-20006). The opinion and assertions contained herein are the private views of the authors and are not to be construed as official or as representing the views of the Department of the Army or the Department of Defense.

Author information

Authors and Affiliations

  1. Windber Research Institute, Windber, PA, 15963, USA

    Heather L. Blackburn & Darrell L. Ellsworth

  2. Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA

    Craig D. Shriver

  3. Clinical Breast Care Project, Murtha Cancer Center, 620 Seventh Street, Windber, 15963, PA, USA

    Rachel E. Ellsworth

Authors
  1. Heather L. Blackburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darrell L. Ellsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Craig D. Shriver
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rachel E. Ellsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rachel E. Ellsworth.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blackburn, H.L., Ellsworth, D.L., Shriver, C.D. et al. Role of cytochrome P450 genes in breast cancer etiology and treatment: effects on estrogen biosynthesis, metabolism, and response to endocrine therapy. Cancer Causes Control 26, 319–332 (2015). https://doi.org/10.1007/s10552-014-0519-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-014-0519-7

Keywords

Search

Navigation