Chemoresistance was correlated with elevated expression and activity of indoleamine 2,3-dioxygenase in breast cancer.

Abstract

Indoleamine 2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan leading to the production of immunosuppressive kynurenine and tryptophan exhausting. IDO expression and activity contribute to aggressive tumor growth, inferior therapeutic gain and poor prognosis. The aim of this study was to explore the association between chemoresistance and IDO expression, activity in breast cancer METHODS: Immunohistochemistry was applied for evaluating IDO expression in biopsy tissues. Serum IDO activity was examined via High-performance liquid chromatography (HPLC). Western blots (WB), HPLC and Real-time PCR (RT-PCR) were used to analyze IDO protein, IDO enzyme activity and IDO gene expression in original and paclitaxel-resistant cells respectively. Logistic regression and survival analysis were applied to explore the association between chemoresistance and IDO expression, activity in breast cancer. IDO expression in tumor tissues was associated with serum IDO activity (P = 0.004). Both IDO expression in tumor and serum activity were associated with clinical tumor stage, node stage and estrogen receptor (ER) status (all P < 0.05); clinical response and pathologic complete response (pCR) to NAC were both related to IDO expression and activity prior NAC (all P < 0.05). Multivariate analysis showed IDO activity before NAC was the only independent factor affected pCR (P = 0.032). ROC curves showed that the IDO expression and activity had discriminative ability for predicting the clinical response and pCR. In the prognostic analysis, patients with high IDO expression had significantly impaired overall survival (5year survival rate: 53.57% vs 80.00%) and progression-free survival (5year survival rate: 46.43% vs 72.00%, P = 0.031 and P = 0.046). In vitro, significantly increased IDO protein, IDO mRNA expression and IDO enzyme activity in paclitaxel-resistant cells were demonstrated in comparing of sensitive cells. IDO expression and activity associated with advanced breast cancer, poor response to neoadjuvant chemotherapy and prognosis. IDO expression and activity were significantly increased in paclitaxel-resistant breast cancer cells.