Increased expression of enolase alpha in human breast cancer confers tamoxifen resistance in human breast cancer cells.

Abstract

Enolase-alpha (ENO-1) is a key glycolytic enzyme that has been used as a diagnostic marker to identify human lung cancers. To investigate the role of ENO-1 in breast cancer diagnosis and therapy, the mRNA levels of ENO-1 in 244 tumor and normal paired tissue samples and 20 laser capture-microdissected cell clusters were examined by quantitative real-time PCR analysis. Increased ENO-1 mRNA expression was preferentially detected in estrogen receptor-positive (ER+) tumors (tumor/normal ratio >90-fold) when compared to ER-negative (tumor/normal ratio >20-fold) tumor tissues. The data presented here demonstrate that those patients whose tumors highly expressed ENO-1 had a poor prognosis with greater tumor size (>2 cm, *P = .017), poor nodal status (N > 3, *P = .018), and a shorter disease-free interval (<==1 year, *P < .009). We also found that higher-expressing ENO-1 tumors confer longer distance relapse (tumor/normal ratio = 82.8-92.4-fold) when compared to locoregional relapse (tumor/normal ratio = 43.4-fold) in postsurgical 4-hydroxy-tamoxifen (4-OHT)-treated ER+ patients (*P = .014). These data imply that changes in tumor ENO-1 levels are related to clinical 4-OHT therapeutic outcome. In vitro studies demonstrated that decreasing ENO-1 expression using small interfering RNA (siRNA) significantly augmented 4-OHT (100 nM)-induced cytotoxicity in tamoxifen-resistant (Tam-R) breast cancer cells. These results suggest that downregulation of ENO-1 could be utilized as a novel pharmacological approach for overcoming 4-OHT resistance in breast cancer therapy.

• Authors: Shih-Hsin Tu, Chih-Chiang Chang, Ching-Shyang Chen, Ka-Wai Tam, Ying-Jan Wang, Chia-Hwa Lee, Hsiao-Wei Lin, Tzu-Chun Cheng, Ching-Shui Huang, Jan-Show Chu, Neng-Yao Shih, Li-Ching Chen, Sy-Jye Leu, Yuan-Soon Ho, Chih-Hsiung Wu
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 121 Issue 3 Pg. 539-53 (Jun 2010) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 19655245 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Biomarkers, Tumor
• DNA-Binding Proteins
• Estrogen Receptor alpha
• NF-kappa B
• RNA, Messenger
• RNA, Small Interfering
• Tumor Suppressor Proteins
• Tamoxifen
• ENO1 protein, human
• Phosphopyruvate Hydratase

Topics

• Adult
• Aged
• Antineoplastic Agents, Hormonal (pharmacology)
• Biomarkers, Tumor (antagonists & inhibitors, metabolism)
• Breast Neoplasms (drug therapy, pathology)
• Case-Control Studies
• Cells, Cultured
• DNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Estrogen Receptor alpha (metabolism)
• Female
• Humans
• Middle Aged
• NF-kappa B (metabolism)
• Phosphopyruvate Hydratase (antagonists & inhibitors, metabolism)
• Prognosis
• RNA, Messenger (analysis)
• RNA, Small Interfering
• Survival Analysis
• Tamoxifen (pharmacology)
• Tumor Suppressor Proteins (antagonists & inhibitors, metabolism)