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. 2003 Dec;40(12):885–890. doi: 10.1136/jmg.40.12.885

Somatic instability of the DNA sequences encoding the polymorphic polyglutamine tract of the AIB1 gene

P Dai 1, L Wong 1
PMCID: PMC1735346  PMID: 14684685

Abstract

Background: AIB1 contains a polymorphic polyglutamine tract (poly Q) that is encoded by a trinucleotide CAG repeat. Previously there have been conflicting results regarding the effect of the poly Q tract length on breast cancer. Since poly Q is not encoded by a perfect CAG repeat, the heterozygous polymorphic alleles need to be resolved, to understand the exact DNA sequences encoding poly Q.

Methods: Poly Q encoding sequences of AIB1 from 107 DNA samples, including breast cancer cell lines, sporadic primary breast tumours, and blood samples from BRCA1/BRCA2 mutation carriers and the general population, were resolved by PCR/cloning followed by sequencing of each individual clone.

Results: 25 distinct poly Q encoding sequence patterns were found. More than two distinct sequence patterns were found in a significantly higher proportion of tumours and cell lines than that of the general population, suggesting somatic instability. A significantly higher proportion of cancer cell lines or primary breast tumours than that of the general population contained rare sequence patterns. The proportion of sporadic breast tumours having at least one allele ⩽27 repeats is significantly higher than that in the blood of BRCA1/BRCA2 mutation carrier breast cancer patients or the general population.

Conclusion: The poly Q encoding DNA sequences are somatically unstable in tumour tissues and cell lines. A missense mutation and a very short glutamine repeat in primary tumours suggests that AIB1 activity may be modulated through poly Q, which in turn plays a role in the cotransactivation of gene expressions in breast cancers.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anzick S. L., Kononen J., Walker R. L., Azorsa D. O., Tanner M. M., Guan X. Y., Sauter G., Kallioniemi O. P., Trent J. M., Meltzer P. S. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science. 1997 Aug 15;277(5328):965–968. doi: 10.1126/science.277.5328.965. [DOI] [PubMed] [Google Scholar]
  2. Gerber H. P., Seipel K., Georgiev O., Höfferer M., Hug M., Rusconi S., Schaffner W. Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science. 1994 Feb 11;263(5148):808–811. doi: 10.1126/science.8303297. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Guan X. Y., Xu J., Anzick S. L., Zhang H., Trent J. M., Meltzer P. S. Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer. Cancer Res. 1996 Aug 1;56(15):3446–3450. [PubMed] [Google Scholar]
  5. Haiman C. A., Hankinson S. E., Spiegelman D., Colditz G. A., Willett W. C., Speizer F. E., Brown M., Hunter D. J. Polymorphic repeat in AIB1 does not alter breast cancer risk. Breast Cancer Res. 2000 Jun 19;2(5):378–385. doi: 10.1186/bcr82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hayashi Y., Yamamoto M., Ohmori S., Kikumori T., Imai T., Funahashi H., Seo H. Polymorphism of homopolymeric glutamines in coactivators for nuclear hormone receptors. Endocr J. 1999 Apr;46(2):279–284. doi: 10.1507/endocrj.46.279. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Klement I. A., Skinner P. J., Kaytor M. D., Yi H., Hersch S. M., Clark H. B., Zoghbi H. Y., Orr H. T. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell. 1998 Oct 2;95(1):41–53. doi: 10.1016/s0092-8674(00)81781-x. [DOI] [PubMed] [Google Scholar]
  9. Koivisto P., Hyytinen E., Palmberg C., Tammela T., Visakorpi T., Isola J., Kallioniemi O. P. Analysis of genetic changes underlying local recurrence of prostate carcinoma during androgen deprivation therapy. Am J Pathol. 1995 Dec;147(6):1608–1614. [PMC free article] [PubMed] [Google Scholar]
  10. Koshy B. T., Zoghbi H. Y. The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis. Brain Pathol. 1997 Jul;7(3):927–942. doi: 10.1111/j.1750-3639.1997.tb00894.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Lahiri D. K., Nurnberger J. I., Jr A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991 Oct 11;19(19):5444–5444. doi: 10.1093/nar/19.19.5444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Li H., Gomes P. J., Chen J. D. RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8479–8484. doi: 10.1073/pnas.94.16.8479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Oñate S. A., Tsai S. Y., Tsai M. J., O'Malley B. W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995 Nov 24;270(5240):1354–1357. doi: 10.1126/science.270.5240.1354. [DOI] [PubMed] [Google Scholar]
  15. Paulson H. L. Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold. Am J Hum Genet. 1999 Feb;64(2):339–345. doi: 10.1086/302269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Rebbeck T. R., Wang Y., Kantoff P. W., Krithivas K., Neuhausen S. L., Godwin A. K., Daly M. B., Narod S. A., Brunet J. S., Vesprini D. Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history. Cancer Res. 2001 Jul 15;61(14):5420–5424. [PubMed] [Google Scholar]
  17. Saudou F., Finkbeiner S., Devys D., Greenberg M. E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell. 1998 Oct 2;95(1):55–66. doi: 10.1016/s0092-8674(00)81782-1. [DOI] [PubMed] [Google Scholar]
  18. Shibata A., Hayashi Y., Imai T., Funahashi H., Nakao A., Seo H. Somatic gene alteration of AIB1 gene in patients with breast cancer. Endocr J. 2001 Apr;48(2):199–204. doi: 10.1507/endocrj.48.199. [DOI] [PubMed] [Google Scholar]
  19. Takeshita A., Cardona G. R., Koibuchi N., Suen C. S., Chin W. W. TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1. J Biol Chem. 1997 Oct 31;272(44):27629–27634. doi: 10.1074/jbc.272.44.27629. [DOI] [PubMed] [Google Scholar]
  20. Visakorpi T., Hyytinen E., Koivisto P., Tanner M., Keinänen R., Palmberg C., Palotie A., Tammela T., Isola J., Kallioniemi O. P. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995 Apr;9(4):401–406. doi: 10.1038/ng0495-401. [DOI] [PubMed] [Google Scholar]
  21. Voegel J. J., Heine M. J., Zechel C., Chambon P., Gronemeyer H. TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J. 1996 Jul 15;15(14):3667–3675. [PMC free article] [PubMed] [Google Scholar]

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