Increased expression of enolase alpha in human breast cancer confers tamoxifen resistance in human breast cancer cells.
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.
Tu
Shih-Hsin
SH
Department of Surgery, Cathay General Hospital, Taipei, Taiwan.
Chang
Chih-Chiang
CC
Chen
Ching-Shyang
CS
Tam
Ka-Wai
KW
Wang
Ying-Jan
YJ
Lee
Chia-Hwa
CH
Lin
Hsiao-Wei
HW
Cheng
Tzu-Chun
TC
Huang
Ching-Shui
CS
Chu
Jan-Show
JS
Shih
Neng-Yao
NY
Chen
Li-Ching
LC
Leu
Sy-Jye
SJ
Ho
Yuan-Soon
YS
Wu
Chih-Hsiung
CH
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D016019:Survival Analysis; D013629:Tamoxifen / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase