Journal of the National Cancer Institute Advance Access published online on November 13, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm207
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Molecular Basis for Estrogen Receptor 
Deficiency in BRCA1-Linked Breast Cancer
Affiliations of authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, U.K. (AMH, JJG, MMM, JEQ, GES, CRJ, PGJ, PBM, DPH); School of Medicine and Medical Science (P.A. Dervan, WYC, AM), and the Conway Institute of Biomolecular and Biomedical Science (WYC, AM), University College Dublin, Dublin, Ireland; Department of Pathology, Mater Misericordiae Hospital, Dublin, Ireland (P. A. Dervan); Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN (FJC); Department of Haematology and Oncology, Trinity College, St James's Hospital, Dublin, Ireland (P. A. Daly); Department of Histopathology, Education and Research Centre, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland (EK); Almac Diagnostics, Craigavon, U.K. (SMF, JMM, ANS)
Correspondence to: D. Paul Harkin, PhD, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast, Northern Ireland, BT9 7BL, U.K. (e-mail: d.harkin{at}qub.ac.uk).
Background: BRCA1-mutant breast tumors are typically estrogen receptor alpha (ER
) negative, whereas most sporadic tumors express wild-type BRCA1 and are ER positive. We examined a possible mechanism for the observed ER-negative phenotype of BRCA1-mutant tumors.
Methods: We used a breast cancer disease–specific microarray to identify transcripts that were differentially expressed between paraffin-embedded samples of 17 BRCA1-mutant and 14 sporadic breast tumors. We measured the mRNA levels of estrogen receptor 1 (ESR1) (the gene encoding ER), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ER protein expression was assessed in human breast cancer HCC1937 cells that were stably reconstituted with wild-type BRCA1 expression construct and in human breast cancer T47D and MCF-7 cells transiently transfected with BRCA1-specific short-interfering RNA (siRNA). Chromatin immunoprecipitation assays were performed to determine if BRCA1 binds the ESR1 promoter and to identify other interacting proteins. Sensitivity to the antiestrogen drug fulvestrant was examined in T47D and MCF-7 cells transfected with BRCA1-specific siRNA. All statistical tests were two-sided.
Results: Mean ESR1 gene expression was 5.4-fold lower in BRCA1-mutant tumors than in sporadic tumors (95% confidence interval [CI] = 2.6-fold to 40.1-fold, P = .0019). The transcription factor Oct-1 recruited BRCA1 to the ESR1 promoter, and both BRCA1 and Oct-1 were required for ER expression. BRCA1-depleted breast cancer cells expressing exogenous ER were more sensitive to fulvestrant than BRCA1-depleted cells transfected with empty vector (T47D cells, the mean concentration of fulvestrant that inhibited the growth of 40% of the cells [IC40] for empty vector versus ER: >10–5 versus 8.0 x 10–9 M [95% CI = 3.1 x 10–10 to 3.2 x 10–6 M]; MCF-7 cells, mean IC40 for empty vector versus ER: >10–5 versus 4.9 x 10–8 M [95% CI = 2.0 x 10–9 to 3.9 x 10–6 M]).
Conclusions: BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ER expression.
| CONTEXT AND CAVEATS Prior knowledge
BRCA1-mutant breast tumors are typically estrogen receptor alpha (ER Study design
In vitro studies in human breast cancer cells were used to examine the mechanism for the disparity in ER Contribution
BRCA1-mutant tumors fail to express ER Implications
BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ER Limitations
A small number of human breast tumors were used for molecular profiling. The mechanism by which some of the BRCA1-mutant tumors retained ER
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Manuscript received May 7, 2007; revised September 12, 2007; accepted October 1, 2007.
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Deficiency in BRCA1-Linked Breast Cancer
J Natl Cancer Inst 2008 100: 752-753.
J Natl Cancer Inst 2007 99: 1655-1657.
J Natl Cancer Inst 2007 99: 1653.
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