Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat.
Open accessAbstract
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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Mutations in AR have been linked with breast cancer in men.
“Moreover, mutations in AR have been linked with breast cancer in men (199).”
From Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone (2003) · cites this paper as [199]
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- Authors
- Rebbeck, T. R., Kantoff, P. W., Krithivas, K., Neuhausen, S., Blackwood, M. A., Godwin, A. K., Daly, M. B., Narod, S. A., Garber, J. E., Lynch, H. T., Weber, B. L., & Brown, M.
- Affiliations
- University of Pennsylvania (US)
- Harvard University (US)
- Creighton University (US)
- Fox Chase Cancer Center (US)
- Corresponding author
- Rebbeck, Timothy R.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 1999-05
- Volume
- 64
- Issue
- 5
- Pages
- 1371-1377
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1377873
- OpenAlex
- W2105956205
- Cited by
- 252
- References
- 24
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 1 · 2015: 5 · 2014: 1 · 2013: 1 · 2012: 8
- FWCI
- 18.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Creighton Digital Repository (CDR) (submittedVersion)
- Funders
- National Institutes of Health (5r01ca057601-07)
- National Cancer Institute (CA-57601, CA737370)
- National Institute of Environmental Health Sciences (ES97939)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
- Keywords
- BRCA1, breast cancer risk, androgen receptor, CAG repeat polymorphism, germline mutation carriers, age at breast cancer diagnosis, androgen signaling, hormone signaling, genetic susceptibility, exon 1
- MeSH terms
- Adult, Aged, Breast Neoplasms, Female, Heterozygote, Humans, Middle Aged, Receptors, Androgen, Signal Transduction, Proportional Hazards Models, Polymerase Chain Reaction, Germ-Line Mutation, Trinucleotide Repeats, Genes, BRCA1, Genetic Predisposition to Disease
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