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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 {alpha} Deficiency in BRCA1-Linked Breast Cancer

Alison M. Hosey, Julia J. Gorski, Margaret M. Murray, Jennifer E. Quinn, Wen Y. Chung, Gail E. Stewart, Colin R. James, Susan M. Farragher, Jude M. Mulligan, Alistair N. Scott, Peter A. Dervan, Patrick G. Johnston, Fergus J. Couch, Peter A. Daly, Elaine Kay, Amanda McCann, Paul B. Mullan, D. Paul Harkin

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{alpha}) negative, whereas most sporadic tumors express wild-type BRCA1 and are ER{alpha} positive. We examined a possible mechanism for the observed ER{alpha}-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{alpha}), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ER{alpha} 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{alpha} expression. BRCA1-depleted breast cancer cells expressing exogenous ER{alpha} 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{alpha}: >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{alpha}: >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{alpha} expression.


CONTEXT AND CAVEATS

Prior knowledge

BRCA1-mutant breast tumors are typically estrogen receptor alpha (ER{alpha}) negative, whereas most sporadic tumors express wild-type BRCA1 and are ER{alpha} positive. The molecular basis for the ER{alpha}-negative phenotype of BRCA1-mutant tumors has not been defined.

Study design

In vitro studies in human breast cancer cells were used to examine the mechanism for the disparity in ER{alpha} expression identified by molecular profiling of 17 BRCA1-mutant and 14 sporadic human breast tumors. The sensitivity of human breast cancer cells to the antiestrogen drug fulvestrant was examined as function of BRCA1 expression.

Contribution

BRCA1-mutant tumors fail to express ER{alpha} due to the loss of BRCA1-mediated transcriptional activation of the gene encoding ER{alpha}. Expression of exogenous ER{alpha} in BRCA1-depleted breast cancer cells increased their sensitivity to fulvestrant.

Implications

BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ER{alpha} expression.

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{alpha} positivity is not known.

 
Manuscript received May 7, 2007; revised September 12, 2007; accepted October 1, 2007.


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Correspondence about this Article

Re: Molecular Basis for Estrogen Receptor {alpha} Deficiency in BRCA1-Linked Breast Cancer
Lara Lusa, Bernard Peissel, Siranoush Manoukian, Edoardo Marchesi, Paolo Radice, Marco A. Pierotti, and Manuela Gariboldi
J Natl Cancer Inst 2008 100: 752-753. [Extract] [Full Text] [PDF]

Editorial about this Article

Estrogen Receptors in BRCA1-Mutant Breast Cancer: Now You See Them, Now You Don’t
V. Craig Jordan
J Natl Cancer Inst 2007 99: 1655-1657. [Extract] [Full Text] [PDF]

Related Article in JNCI

IN THIS ISSUE
J Natl Cancer Inst 2007 99: 1653. [Extract] [Full Text] [PDF]



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