Catechol-O-methyltransferase: a dual-role player in different breast cancer subtypes?
|Fakulta / Pracoviště MU|
|Popis||Catechol-O-methyltransferase (COMT) plays an essential role in detoxification of catechols by transferring the methyl group from S-adenosyl-L-methionine to the substrate. In breast cancer, it catalyses methylation of oestrogen metabolites to block their oestrogenicity which prevents their oxidation to carcinogenic quinones. In this study we investigated whether this tumour suppressor role is limited to oestrogen receptor dependent breast cancer, or whether it has a general validity. A differential cell surface proteomics analysis with SILAC-LC-MS quantification was performed on MDA-MB-231 breast cancer cell line and its clone selected for higher migration capacity. Analysis of migration and invasiveness of MCF7 cells stably transfected with COMT was performed using Transwell assay. The protein-level expression of COMT in different breast cancer subtypes was determined by next-generation, data independent acquisition based proteomics (96 patients) and immunohistochemistry (621 patients). A quantitative cell surface proteomics identified the membrane-bound isoform of COMT as a cell surface protein overexpressed in a more migrating clone of MDA-MB-231 cells, indicating the association of COMT with cell motility in triple negative breast cancer. On the other hand, overexpression of COMT in MCF-7 cells decreased cell migration and invasiveness, supporting tumour suppressor role in oestrogen receptor dependent breast cancer. Analysis of 96 primary breast cancer tumours using next generation proteomics showed increased COMT protein levels in more aggressive tumours: in grade 3 vs. grade 1, in luminal B vs. luminal A, in triple negative vs. luminal A, and in triple negative lymph node positive vs. triple negative lymph node negative tumours. Based on our results, we hypothesize a dual role of COMT in breast cancer: while tumour suppressor role is further supported by our data in ER+ breast cancer cells, in tissues COMT seems to be associated with more aggressive phenotype, namely in ER independent, triple negative breast cancer. It is thus evident that the dominance of catecholoestrogen methylation activity may be limited to ER dependent breast cancer. This may alter the perspective how COMT is considered as a potential diagnostic or therapeutic target.|