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

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.

[1]  L Pinsky,et al.  Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. , 1995, Human molecular genetics.

[2]  M. Dowsett,et al.  Identification of an exon 3 deletion splice variant androgen receptor mRNA in human breast cancer , 1997, International journal of cancer.

[3]  H. Scher,et al.  Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. , 1996, The Journal of clinical endocrinology and metabolism.

[4]  B. Pasternack,et al.  Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. , 1997, American journal of epidemiology.

[5]  H. Nguyen,et al.  Hormone-dependent regulation of BRCA1 in human breast cancer cells. , 1995, Cancer research.

[6]  K. Fischbeck,et al.  Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy , 1991, Nature.

[7]  D. Easton,et al.  Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. , 1995, American journal of human genetics.

[8]  L. Cannon-Albright,et al.  Risk modifiers in carriers of brca1 mutations , 1995, International journal of cancer.

[9]  D. Clayton,et al.  Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation , 1995, Nature Genetics.

[10]  F. Ghadessy,et al.  Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. , 1997, The Journal of clinical endocrinology and metabolism.

[11]  P. Hartge,et al.  The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. , 1997, The New England journal of medicine.

[12]  A. Futreal,et al.  BRCA1 expression is not directly responsive to estrogen , 1997, Oncogene.

[13]  S. Piantadosi,et al.  Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[14]  N. Chamberlain,et al.  The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. , 1994, Nucleic acids research.

[15]  P. Kantoff,et al.  The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[16]  L. J. Wei,et al.  The Robust Inference for the Cox Proportional Hazards Model , 1989 .

[17]  C. Sonnenschein,et al.  Androgen-induced inhibition of proliferation in human breast cancer MCF7 cells transfected with androgen receptor. , 1997, Endocrinology.

[18]  G. Coetzee,et al.  Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. , 1997, Journal of the National Cancer Institute.

[19]  A. Segaloff,et al.  Androgenic therapy for advanced breast cancer in women. A report of the cooperative breast cancer group. , 1973, JAMA.

[20]  K. Schulz,et al.  Androgen receptor mediated growth control of breast cancer and endometrial cancer modulated by antiandrogen- and androgen-like steroids , 1996, The Journal of Steroid Biochemistry and Molecular Biology.

[21]  R. Eeles,et al.  Androgen receptor polymorphisms: Association with prostate cancer risk, relapse and overall survival , 1999, International journal of cancer.

[22]  D. Horsfall,et al.  Androgens induce divergent proliferative responses in human breast cancer cell lines , 1995, The Journal of Steroid Biochemistry and Molecular Biology.