Immunoexpression of Multidrug-Resistance Protein 2 and Cyclooxygenase 2 in Medullary Thyroid Carcinomas

Abstract

Chemoresistance is due to the expression of multidrug-resistance proteins (MRPs). Cyclooxygenase 2 (COX2), a key enzyme in prostaglandins synthesis, upregulates MRP1. MRP1 is overexpressed in medullary thyroid carcinomas (MTCs), but it is not involved in resistance to doxorubicin and cisplatin, which are commonly used in MTC treatment. MRP2 is specifically involved in resistance to both chemotherapeutic agents, but no data exist on the expression of MRP2 and COX2 in MTC. To evaluate MRP2 and COX2 expressions in MTC. We analyzed immunohistochemical expression of MRP2 and COX2 in 12 MTCs and in 6 lymph node metastases. Results were correlated with pTNM and clinical stage. MRP2 and COX2 expressions were observed only in tumor samples and metastases. Nine MTCs, all pTNM stage T4, were positive for MRP2, whereas 3 MTCs, pTNM stages T2 and T3, were unreactive for MRP2. Six metastatic MTCs at stage T4 showed higher proportion of MRP2+ cells, compared with primary tumors. All 12 MTCs were positive for COX2. Three MTCs, pTNM stage T2 and T3, showed COX2 positivity in all cells. The proportion of COX2+ cells decreased with increased pTNM stage. Four out of 6 metastatic MTCs, stage T4, showed a lower proportion of COX2+ cells, compared with primary tumors. The proportion of MRP2+ cells was inversely related to the proportion of COX2+ cells. MRP2 and COX2 expression correlated with pTNM stage. High MRP2 and low COX2 expression may explain resistance to doxorubicin and cisplatin, which is observed in advanced stage MTC. Evaluation of the expression pattern of these 2 proteins may be useful to predict chemosensitivity of these types of tumors.