+331G/A variant in the progesterone receptor gene, postmenopausal hormone use and risk of breast cancer
Correction(s) for this article
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Erratum
- Volume 125Issue 10International Journal of Cancer
- pages: 2487-2487
- First Published online: August 12, 2009
Corresponding Author
Joanne Kotsopoulos
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Fax: 617-525-2008.
Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USASearch for more papers by this authorShelley S. Tworoger
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Search for more papers by this authorImmaculata DeVivo
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Search for more papers by this authorSusan E. Hankinson
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Search for more papers by this authorDavid J. Hunter
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Search for more papers by this authorWalter C. Willett
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Department of Nutrition, Harvard School of Public Health, Boston, MA
Search for more papers by this authorWendy Y. Chen
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Search for more papers by this authorCorresponding Author
Joanne Kotsopoulos
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Fax: 617-525-2008.
Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USASearch for more papers by this authorShelley S. Tworoger
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Search for more papers by this authorImmaculata DeVivo
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Search for more papers by this authorSusan E. Hankinson
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Search for more papers by this authorDavid J. Hunter
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Search for more papers by this authorWalter C. Willett
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Epidemiology, Harvard School of Public Health, Boston, MA
Department of Nutrition, Harvard School of Public Health, Boston, MA
Search for more papers by this authorWendy Y. Chen
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Search for more papers by this authorAbstract
A functional promoter polymorphism in the progesterone receptor (PR) gene previously has been associated with an increased risk of postmenopausal breast cancer. Whether the relationship between genetic variation in PR and risk of breast cancer is modified by postmenopausal hormone (PMH) use is unknown. Thus, we conducted a case–control study nested within the prospective Nurses' Health Study to evaluate if the risk of breast cancer associated with having the +331 A risk allele was modified by PMH use. Genotyping of this SNP was available for 1,664 postmenopausal breast cancer cases and 2,391 controls. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer. Women who were carriers of 1 or both variant A alleles had a 31% increased risk of developing breast cancer (95% CI 1.04–1.65). PMH use significantly modified the association between the +331G/A polymorphism and risk (p-interaction <0.05). Among never users of PMH, women who were variant carriers had a significantly increased risk of breast cancer compared to those with the wild-type genotype (OR = 2.57; 95% CI 1.64–4.02). The +331G/A polymorphism was not associated with breast cancer risk among past (OR = 1.23; 95% CI 0.77–1.97) or current (OR = 1.14; 95% CI 0.84–1.56) PMH users. The data from this large prospective study provide evidence for a 2-fold increased risk of developing postmenopausal breast cancer among never users of PMH with the +331G/A SNP. This finding adds to the evidence that the PR has an important etiologic role in breast cancer and should be evaluated in future studies. © 2009 UICC
References
- 1 Lydon JP,DeMayo FJ,Funk CR,Mani SK,Hughes AR,Montgomery CA,Jr,Shyamala G,Conneely OM,O'Malley BW. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 1995; 9: 2266–78.
- 2 Kastner P,Krust A,Turcotte B,Stropp U,Tora L,Gronemeyer H,Chambon P. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 1990; 9: 1603–14.
- 3 Conneely OM,Maxwell BL,Toft DO,Schrader WT,O'Malley BW. The A and B forms of the chicken progesterone receptor arise by alternate initiation of translation of a unique mRNA. Biochem Biophys Res Commun 1987; 149: 493–501.
- 4 Conneely OM,Kettelberger DM,Tsai MJ,Schrader WT,O'Malley BW. The chicken progesterone receptor A and B isoforms are products of an alternate translation initiation event. J Biol Chem 1989; 264: 14062–4.
- 5 Wen DX,Xu YF,Mais DE,Goldman ME,McDonnell DP. The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells. Mol Cell Biol 1994; 14: 8356–64.
- 6 Sartorius CA,Melville MY,Hovland AR,Tung L,Takimoto GS,Horwitz KB. A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. Mol Endocrinol 1994; 8: 1347–60.
- 7 Giangrande PH,Kimbrel EA,Edwards DP,McDonnell DP. The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol Cell Biol 2000; 20: 3102–15.
- 8 Horwitz KB. The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer? Endocr Rev 1992; 13: 146–63.
- 9 Richer JK,Jacobsen BM,Manning NG,Abel MG,Wolf DM,Horwitz KB. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 2002; 277: 5209–18.
- 10 Conneely OM,Lydon JP,De Mayo F,O'Malley BW. Reproductive functions of the progesterone receptor. J Soc Gynecol Investig 2000; 7: S25–S32.
- 11 Daniel CW,Smith GH. The mammary gland: a model for development. J Mammary Gland Biol Neoplasia 1999; 4: 3–8.
- 12 De Vivo I,Huggins GS,Hankinson SE,Lescault PJ,Boezen M,Colditz GA,Hunter DJ. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci USA 2002; 99: 12263–8.
- 13 Huggins GS,Wong JY,Hankinson SE,De Vivo I. GATA5 activation of the progesterone receptor gene promoter in breast cancer cells is influenced by the +331G/A polymorphism. Cancer Res 2006; 66: 1384–90.
- 14 Cramer DW,Hornstein MD,McShane P,Powers RD,Lescault PJ,Vitonis AF,De Vivo I. Human progesterone receptor polymorphisms and implantation failure during in vitro fertilization. Am J Obstet Gynecol 2003; 189: 1085–92.
- 15 Mote PA,Bartow S,Tran N,Clarke CL. Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat 2002; 72: 163–72.
- 16 Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047–59.
- 17 Rossouw JE,Anderson GL,Prentice RL,LaCroix AZ,Kooperberg C,Stefanick ML,Jackson RD,Beresford SA,Howard BV,Johnson KC,Kotchen JM,Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33.
- 18 Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362: 419–27.
- 19 Ross RK,Paganini-Hill A,Wan PC,Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000; 92: 328–32.
- 20 Chen WY,Hankinson SE,Schnitt SJ,Rosner BA,Holmes MD,Colditz GA. Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma. Cancer 2004; 101: 1490–500.
- 21 Colditz GA,Hankinson SE,Hunter DJ,Willett WC,Manson JE,Stampfer MJ,Hennekens C,Rosner B,Speizer FE. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332: 1589–93.
- 22 Mulac-Jericevic B,Mullinax RA,DeMayo FJ,Lydon JP,Conneely OM. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 2000; 289: 1751–4.
- 23 Colditz GA. The nurse's health study: a cohort of US women followed since 1976. J Am Med Womens Assoc 1995; 50: 40–4.
- 24 Colditz GA,Manson JE,Hankinson SE. The Nurse's Health Study: 20-year contribution to the understanding of health among women. JWomens Health 1997; 6: 49–62.
- 25 Colditz GA,Hankinson SE. The Nurse's Health Study: lifestyle and health among women. Nat Rev Cancer 2005; 5: 388–96.
- 26 Hankinson SE,Willett WC,Manson JE,Hunter DJ,Colditz GA,Stampfer MJ,Longcope C,Speizer FE. Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst 1995; 87: 1297–302.
- 27 Tworoger SS,Missmer SA,Barbieri RL,Willett WC,Colditz GA,Hankinson SE. Plasma sex hormone concentrations and subsequent risk of breast cancer among women using postmenopausal hormones. J Natl Cancer Inst 2005; 97: 595–602.
- 28 Tamimi RM,Cox D,Kraft P,Colditz GA,Hankinson SE,Hunter DJ. Breast cancer susceptibility loci and mammographic density. Breast Cancer Res 2008; 10: R66.
- 29 Byng JW,Boyd NF,Little L,Lockwood G,Fishell E,Jong RA,Yaffe MJ. Symmetry of projection in the quantitative analysis of mammographic images. Eur J Cancer Prev 1996; 5: 319–27.
- 30 Byrne C. Mammographic density and breast cancer risk: the evolution of assessment techniques and implications for understanding breast cancer. Semin Breast Dis 1999; 2: 301–14.
- 31 Hankinson SE,Willett WC,Manson JE,Colditz GA,Hunter DJ,Spiegelman D,Barbieri RL,Speizer FE. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998; 90: 1292–9.
- 32 Haiman CA,Hankinson SE,Spiegelman D,Colditz GA,Willett WC,Speizer FE,Kelsey KT,Hunter DJ. The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer. Cancer Res 1999; 59: 1015–20.
- 33 De Vivo I,Hankinson SE,Colditz GA,Hunter DJ. A functional polymorphism in the progesterone receptor gene is associated with an increase in breast cancer risk. Cancer Res 2003; 63: 5236–8.
- 34 Pearce CL,Wu AH,Gayther SA,Bale AE,Beck PA,Beesley J,Chanock S,Cramer DW,DiCioccio R,Edwards R,Fredericksen ZS,Garcia-Closas M, et al. Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis. Br J Cancer 2008; 98: 282–8.
- 35 van Duijnhoven FJ,Peeters PH,Warren RM,Bingham SA,Uitterlinden AG,van Noord PA,Monninkhof EM,Grobbee DE,van Gils CH. Influence of estrogen receptor α and progesterone receptor polymorphisms on the effects of hormone therapy on mammographic density. Cancer Epidemiol Biomarkers Prev 2006; 15: 462–7.
- 36 Feigelson HS,Rodriguez C,Jacobs EJ,Diver WR,Thun MJ,Calle EE. No association between the progesterone receptor gene +331G/A polymorphism and breast cancer. Cancer Epidemiol Biomarkers Prev 2004; 13: 1084–5.
- 37 Gold B,Kalush F,Bergeron J,Scott K,Mitra N,Wilson K,Ellis N,Huang H,Chen M,Lippert R,Halldorsson BV,Woodworth B, et al. Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Cancer Res 2004; 64: 8891–900.
- 38 Fernandez LP,Milne RL,Barroso E,Cuadros M,Arias JI,Ruibal A,Benitez J,Ribas G. Estrogen and progesterone receptor gene polymorphisms and sporadic breast cancer risk: a Spanish case-control study. Int J Cancer 2006; 119: 467–71.
- 39 Romano A,Lindsey PJ,Fischer DC,Delvoux B,Paulussen AD,Janssen RG,Kieback DG. Two functionally relevant polymorphisms in the human progesterone receptor gene (+331 G/A and progins) and the predisposition for breast and/or ovarian cancer. Gynecol Oncol 2006; 101: 287–95.
- 40 Pooley KA,Healey CS,Smith PL,Pharoah PD,Thompson D,Tee L,West J,Jordan C,Easton DF,Ponder BA,Dunning AM. Association of the progesterone receptor gene with breast cancer risk: a single-nucleotide polymorphism tagging approach. Cancer Epidemiol Biomarkers Prev 2006; 15: 675–82.
- 41 Johnatty SE,Spurdle AB,Beesley J,Chen X,Hopper JL,Duffy DL,Chenevix-Trench G. Progesterone receptor polymorphisms and risk of breast cancer: results from two Australian breast cancer studies. Breast Cancer Res Treat 2008; 109: 91–9.
- 42 Hunter DJ,Kraft P,Jacobs KB,Cox DG,Yeager M,Hankinson SE,Wacholder S,Wang Z,Welch R,Hutchinson A,Wang J,Yu K, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007; 39: 870–4.
- 43 Rowan BG,Garrison N,Weigel NL,O'Malley BW. 8-Bromo-cyclic AMP induces phosphorylation of two sites in SRC-1 that facilitate ligand-independent activation of the chicken progesterone receptor and are critical for functional cooperation between SRC-1 and CREB binding protein. Mol Cell Biol 2000; 20: 8720–30.
- 44 Migliaccio A,Piccolo D,Castoria G,Di Domenico M,Bilancio A,Lombardi M,Gong W,Beato M,Auricchio F. Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J 1998; 17: 2008–18.
- 45 Hopp TA,Weiss HL,Hilsenbeck SG,Cui Y,Allred DC,Horwitz KB,Fuqua SA. Breast cancer patients with progesterone receptor PR-A-rich tumors have poorer disease-free survival rates. Clin Cancer Res 2004; 10: 2751–60.
- 46 Lofgren L,Sahlin L,Von Schoultz B,Fernstad R,Skoog L,Von Schoultz E. Expression of sex steroid receptor subtypes in normal and malignant breast tissue—a pilot study in postmenopausal women. Acta Oncol 2006; 45: 54–60.
- 47 Mulac-Jericevic B,Lydon JP,DeMayo FJ,Conneely OM. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci USA 2003; 100: 9744–9.
- 48 Siiteri PK. Adipose tissue as a source of hormones. Am J Clin Nutr 1987; 45: 277–82.
- 49 Huang Z,Hankinson SE,Colditz GA,Stampfer MJ,Hunter DJ,Manson JE,Hennekens CH,Rosner B,Speizer FE,Willett WC. Dual effects of weight and weight gain on breast cancer risk. JAMA 1997; 278: 1407–11.
- 50 Morimoto LM,White E,Chen Z,Chlebowski RT,Hays J,Kuller L,Lopez AM,Manson J,Margolis KL,Muti PC,Stefanick ML,McTiernan A. Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health Initiative (United States). Cancer Causes Control 2002; 13: 741–51.