PMID- 18000219 OWN - NLM STAT- MEDLINE DCOM- 20071207 LR - 20220129 IS - 1460-2105 (Electronic) IS - 0027-8874 (Print) IS - 0027-8874 (Linking) VI - 99 IP - 22 DP - 2007 Nov 21 TI - Molecular basis for estrogen receptor alpha deficiency in BRCA1-linked breast cancer. PG - 1683-94 AB - 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. FAU - Hosey, Alison M AU - Hosey AM AD - Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast, Northern Ireland, BT9 7BL, UK. FAU - Gorski, Julia J AU - Gorski JJ FAU - Murray, Margaret M AU - Murray MM FAU - Quinn, Jennifer E AU - Quinn JE FAU - Chung, Wen Y AU - Chung WY FAU - Stewart, Gail E AU - Stewart GE FAU - James, Colin R AU - James CR FAU - Farragher, Susan M AU - Farragher SM FAU - Mulligan, Jude M AU - Mulligan JM FAU - Scott, Alistair N AU - Scott AN FAU - Dervan, Peter A AU - Dervan PA FAU - Johnston, Patrick G AU - Johnston PG FAU - Couch, Fergus J AU - Couch FJ FAU - Daly, Peter A AU - Daly PA FAU - Kay, Elaine AU - Kay E FAU - McCann, Amanda AU - McCann A FAU - Mullan, Paul B AU - Mullan PB FAU - Harkin, D Paul AU - Harkin DP LA - eng GR - 2003:596/BCN_/Breast Cancer Now/United Kingdom GR - G0200103/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20071113 PL - United States TA - J Natl Cancer Inst JT - Journal of the National Cancer Institute JID - 7503089 RN - 0 (Antineoplastic Agents, Hormonal) RN - 0 (Estrogen Receptor Modulators) RN - 0 (Estrogen Receptor alpha) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 22X328QOC4 (Fulvestrant) RN - 4TI98Z838E (Estradiol) SB - IM CIN - J Natl Cancer Inst. 2007 Nov 21;99(22):1655-7. PMID: 18000213 CIN - J Natl Cancer Inst. 2008 May 21;100(10):752-3; author reply 753-4. PMID: 18477803 MH - Antineoplastic Agents, Hormonal/*pharmacology MH - Blotting, Northern MH - Breast Neoplasms/*chemistry/drug therapy/*genetics MH - Cell Line, Tumor MH - Estradiol/*analogs & derivatives/pharmacology MH - Estrogen Receptor Modulators/*pharmacology MH - Estrogen Receptor alpha/*deficiency/genetics MH - Female MH - Fulvestrant MH - Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic/drug effects MH - *Gene Silencing MH - *Genes, BRCA1 MH - Humans MH - Immunoblotting MH - Immunoprecipitation MH - *Mutation MH - RNA, Messenger/analysis MH - RNA, Small Interfering MH - Research Design MH - Reverse Transcriptase Polymerase Chain Reaction MH - Transcription, Genetic PMC - PMC6485437 MID - EMS28138 EDAT- 2007/11/15 09:00 MHDA- 2007/12/08 09:00 PMCR- 2019/04/26 CRDT- 2007/11/15 09:00 PHST- 2007/11/15 09:00 [pubmed] PHST- 2007/12/08 09:00 [medline] PHST- 2007/11/15 09:00 [entrez] PHST- 2019/04/26 00:00 [pmc-release] AID - djm207 [pii] AID - 10.1093/jnci/djm207 [doi] PST - ppublish SO - J Natl Cancer Inst. 2007 Nov 21;99(22):1683-94. doi: 10.1093/jnci/djm207. Epub 2007 Nov 13.