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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 May;64(5):1371–1377. doi: 10.1086/302366

Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat.

T R Rebbeck 1, P W Kantoff 1, K Krithivas 1, S Neuhausen 1, M A Blackwood 1, A K Godwin 1, M B Daly 1, S A Narod 1, J E Garber 1, H T Lynch 1, B L Weber 1, M Brown 1
PMCID: PMC1377873  PMID: 10205268

Abstract

Compared with the general population, women who have inherited a germline mutation in the BRCA1 gene have a greatly increased risk of developing breast cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothesize that other genes, particularly those involved in endocrine signaling, may modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the androgen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without breast cancer. We found that women were at significantly increased risk of breast cancer if they carried at least one AR allele with >/=28 CAG repeats. Women who carried an AR-CAG allele of >/=28, >/=29, or >/=30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women who did not carry at least one such allele. All 11 women in our sample who carried at least one AR-CAG allele with >/=29 repeats had breast cancer. Our results support the hypothesis that age at breast cancer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer.

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Selected References

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  1. Birrell S. N., Bentel J. M., Hickey T. E., Ricciardelli C., Weger M. A., Horsfall D. J., Tilley W. D. Androgens induce divergent proliferative responses in human breast cancer cell lines. J Steroid Biochem Mol Biol. 1995 May;52(5):459–467. doi: 10.1016/0960-0760(95)00005-k. [DOI] [PubMed] [Google Scholar]
  2. Birrell S. N., Hall R. E., Tilley W. D. Role of the androgen receptor in human breast cancer. J Mammary Gland Biol Neoplasia. 1998 Jan;3(1):95–103. doi: 10.1023/a:1018730519839. [DOI] [PubMed] [Google Scholar]
  3. Chamberlain N. L., Driver E. D., Miesfeld R. L. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994 Aug 11;22(15):3181–3186. doi: 10.1093/nar/22.15.3181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Easton D. F., Ford D., Bishop D. T. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995 Jan;56(1):265–271. [PMC free article] [PubMed] [Google Scholar]
  5. Gayther S. A., Warren W., Mazoyer S., Russell P. A., Harrington P. A., Chiano M., Seal S., Hamoudi R., van Rensburg E. J., Dunning A. M. Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet. 1995 Dec;11(4):428–433. doi: 10.1038/ng1295-428. [DOI] [PubMed] [Google Scholar]
  6. Giovannucci E., Stampfer M. J., Krithivas K., Brown M., Dahl D., Brufsky A., Talcott J., Hennekens C. H., Kantoff P. W. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3320–3323. doi: 10.1073/pnas.94.7.3320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Goldenberg I. S., Waters N., Ravdin R. S., Ansfield F. J., Segaloff A. Androgenic therapy for advanced breast cancer in women. A report of the cooperative breast cancer group. JAMA. 1973 Mar 12;223(11):1267–1268. [PubMed] [Google Scholar]
  8. Gudas J. M., Nguyen H., Li T., Cowan K. H. Hormone-dependent regulation of BRCA1 in human breast cancer cells. Cancer Res. 1995 Oct 15;55(20):4561–4565. [PubMed] [Google Scholar]
  9. Hackenberg R., Schulz K. D. Androgen receptor mediated growth control of breast cancer and endometrial cancer modulated by antiandrogen- and androgen-like steroids. J Steroid Biochem Mol Biol. 1996 Jan;56(1-6):113–117. doi: 10.1016/0960-0760(95)00228-6. [DOI] [PubMed] [Google Scholar]
  10. Hakimi J. M., Schoenberg M. P., Rondinelli R. H., Piantadosi S., Barrack E. R. Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. Clin Cancer Res. 1997 Sep;3(9):1599–1608. [PubMed] [Google Scholar]
  11. Hardy D. O., Scher H. I., Bogenreider T., Sabbatini P., Zhang Z. F., Nanus D. M., Catterall J. F. Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J Clin Endocrinol Metab. 1996 Dec;81(12):4400–4405. doi: 10.1210/jcem.81.12.8954049. [DOI] [PubMed] [Google Scholar]
  12. Ingles S. A., Ross R. K., Yu M. C., Irvine R. A., La Pera G., Haile R. W., Coetzee G. A. Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst. 1997 Jan 15;89(2):166–170. doi: 10.1093/jnci/89.2.166. [DOI] [PubMed] [Google Scholar]
  13. Kazemi-Esfarjani P., Trifiro M. A., Pinsky L. Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. Hum Mol Genet. 1995 Apr;4(4):523–527. doi: 10.1093/hmg/4.4.523. [DOI] [PubMed] [Google Scholar]
  14. La Spada A. R., Wilson E. M., Lubahn D. B., Harding A. E., Fischbeck K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991 Jul 4;352(6330):77–79. doi: 10.1038/352077a0. [DOI] [PubMed] [Google Scholar]
  15. Marks J. R., Huper G., Vaughn J. P., Davis P. L., Norris J., McDonnell D. P., Wiseman R. W., Futreal P. A., Iglehart J. D. BRCA1 expression is not directly responsive to estrogen. Oncogene. 1997 Jan 9;14(1):115–121. doi: 10.1038/sj.onc.1200808. [DOI] [PubMed] [Google Scholar]
  16. Narod S. A., Goldgar D., Cannon-Albright L., Weber B., Moslehi R., Ives E., Lenoir G., Lynch H. Risk modifiers in carriers of BRCA1 mutations. Int J Cancer. 1995 Dec 20;64(6):394–398. doi: 10.1002/ijc.2910640608. [DOI] [PubMed] [Google Scholar]
  17. Struewing J. P., Hartge P., Wacholder S., Baker S. M., Berlin M., McAdams M., Timmerman M. M., Brody L. C., Tucker M. A. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997 May 15;336(20):1401–1408. doi: 10.1056/NEJM199705153362001. [DOI] [PubMed] [Google Scholar]
  18. Szelei J., Jimenez J., Soto A. M., Luizzi M. F., Sonnenschein C. Androgen-induced inhibition of proliferation in human breast cancer MCF7 cells transfected with androgen receptor. Endocrinology. 1997 Apr;138(4):1406–1412. doi: 10.1210/endo.138.4.5047. [DOI] [PubMed] [Google Scholar]
  19. Tut T. G., Ghadessy F. J., Trifiro M. A., Pinsky L., Yong E. L. Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab. 1997 Nov;82(11):3777–3782. doi: 10.1210/jcem.82.11.4385. [DOI] [PubMed] [Google Scholar]
  20. Zeleniuch-Jacquotte A., Bruning P. F., Bonfrer J. M., Koenig K. L., Shore R. E., Kim M. Y., Pasternack B. S., Toniolo P. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol. 1997 Jun 1;145(11):1030–1038. doi: 10.1093/oxfordjournals.aje.a009059. [DOI] [PubMed] [Google Scholar]
  21. Zhu X., Daffada A. A., Chan C. M., Dowsett M. Identification of an exon 3 deletion splice variant androgen receptor mRNA in human breast cancer. Int J Cancer. 1997 Aug 7;72(4):574–580. doi: 10.1002/(sici)1097-0215(19970807)72:4<574::aid-ijc4>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]

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