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Expression Analysis of Estrogen Receptor Coregulators in Breast Carcinoma

Evidence That NCOR1 Expression Is Predictive of the Response to Tamoxifen¹

Laboratoire d’Oncogénétique, Institut National de la Santé et de la Recherche Médicale E0017 [I. G., F. L., S. T., R. L., I. B.] and Département de Médecine [M. T-H.], Centre René Huguenin, F-92211 St-Cloud, and Laboratoire de Génétique Moléculaire, Unité Propre de Recherche et d’Enseignement Supérieur JE 2195, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris V, F-75006 Paris [I. B.], France

Purpose: Dysregulated expression of steroid receptor transcriptional coactivators and corepressors has been implicated in tamoxifen resistance, especially in estrogen receptor (ER) -positive breast cancer patients. Therefore, expression analysis of these ER coregulators may identify new predictors of the response to tamoxifen treatment.

Experimental Design: We measured mRNA levels of 16 coactivator and 11 corepressor genes with a real-time quantitative reverse transcription-PCR method in 14 ER-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 ER-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 ER, ERß, CCND1, and ERBB2.

Results: ER coregulator expression was unrelated to age, histological grade, lymph node status, and macroscopic tumor size. The relationship between mRNA expression of the coregulators, and ER and ß only showed a significant positive correlation between GCN5L2 and ER (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 ER-positive breast tumors.

Commentary

Coregulator Expression and Breast Cancer: Improving the Predictive Power of Estrogen Receptor

Erika Krasnickas Keeton and Myles Brown
Clin. Cancer Res. 2003 9: 1229-1230. [Full Text] [PDF]

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