Expression analysis of estrogen receptor alpha coregulators in breast carcinoma: evidence that NCOR1 expression is predictive of the response to tamoxifen.
OBJECTIVE
Dysregulated expression of steroid receptor transcriptional coactivators and corepressors has been implicated in tamoxifen resistance, especially in estrogen receptor (ER) alpha-positive breast cancer patients. Therefore, expression analysis of these ERalpha coregulators may identify new predictors of the response to tamoxifen treatment.


METHODS
We measured mRNA levels of 16 coactivator and 11 corepressor genes with a real-time quantitative reverse transcription-PCR method in 14 ERalpha-positive breast tumors. Three selected coactivator genes (TIF2, AIB1, and GCN5L2) and two corepressor genes (NCOR1 and MTA1L1) were additionally investigated in a well-characterized series of ERalpha-positive unilateral invasive primary breast tumors from 99 postmenopausal patients who only received tamoxifen as adjuvant hormone therapy after primary surgery. We sought relationships between mRNA levels of the coregulators and those of molecular markers, including ERalpha, ERbeta, CCND1, and ERBB2.


RESULTS
ERalpha coregulator expression was unrelated to age, histological grade, lymph node status, and macroscopic tumor size. The relationship between mRNA expression of the coregulators, and ERalpha and beta only showed a significant positive correlation between GCN5L2 and ERalpha (P = 0.015). mRNA levels of CCND1 correlated with those of all of the coregulators studied (P < 0.05 or trend), whereas ERBB2 mRNA levels only correlated with AIB1 mRNA levels (P = 0.011). Low NCOR1 expression (versus intermediate and high) was associated with significantly shorter relapse-free survival (log-rank test; P = 0.0076). The prognostic significance of low NCOR1 expression persisted in Cox multivariate regression analysis (P = 0.043).


CONCLUSIONS
These findings point to NCOR1 as a promising independent predictor of tamoxifen resistance in patients with ERalpha-positive breast tumors.
Girault
Igor
I
Laboratoire d'Oncogénétique, Institut National de la Santé et de la Recherche Médicale E0017, Centre René Huguenin, F-92211 St-Cloud, France.
Lerebours
Florence
F
Amarir
Samira
S
Tozlu
Sengül
S
Tubiana-Hulin
Michèle
M
Lidereau
Rosette
R
Bièche
Ivan
I
D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis*; D056971:Nuclear Receptor Co-Repressor 1; D016133:Polymerase Chain Reaction; D017698:Postmenopause; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D018931:Antineoplastic Agents, Hormonal; D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D013629:Tamoxifen