Molecular basis for estrogen receptor α 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

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Abstract

Background: BRCA1-mutant breast tumors are typically estrogen receptor alpha (ERα) negative, whereas most sporadic tumors express wild-type BRCA1 and are ERα positive. We examined a possible mechanism for the observed ERα-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 ERα), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ERα 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 ERα expression. BRCA1-depleted breast cancer cells expressing exogenous ERα 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 ERα: >10-5 versus 8.0 × 10-9 M [95% CI = 3.1 × 10-10 to 3.2 × 10-6 M]; MCF-7 cells, mean IC40 for empty vector versus ERα: >10-5 versus 4.9 × 10-8 M [95% CI = 2.0 × 10-9 to 3.9 × 10-6 M]). Conclusions: BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ERα expression.

Original languageEnglish (US)
Pages (from-to)1683-1694
Number of pages12
JournalJournal of the National Cancer Institute
Volume99
Issue number22
DOIs
StatePublished - Nov 2007

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hosey, A. M., Gorski, J. J., Murray, M. M., Quinn, J. E., Chung, W. Y., Stewart, G. E., James, C. R., Farragher, S. M., Mulligan, J. M., Scott, A. N., Dervan, P. A., Johnston, P. G., Couch, F. J., Daly, P. A., Kay, E., McCann, A., Mullan, P. B., & Harkin, D. P. (2007). Molecular basis for estrogen receptor α deficiency in BRCA1-linked breast cancer. Journal of the National Cancer Institute, 99(22), 1683-1694. https://doi.org/10.1093/jnci/djm207