Networking of ion channels with metabolism-related membrane transporters during colorectal and breast cancer progression

Ion Channels and Transporters (ICTs) are progressively emerging as a novel class of membrane proteins expressed in several types of human cancers and regulating the different aspects of cancer cell behavior. One of the ion channels dysregulated in cancers is hERG1 potassium channel and we investigated the role of hERG1 and other ICTs in colorectal and breast cancer. We started with the analysis of a pro-angiogenic signalling pathway involving hERG1 and β1-integrin (reported earlier in vitro) in primary samples from mCRCa (metastatic Colorectal Cancer) patients treated with Bevacizumab (BV). We found that this pro-angiogenic pathway interacts also in mCRC patients and that hERG1 is a positive prognostic biomarker for mCRCa patients treated with BV. Then we studied the role of hERG1 and Kca3.1 potassium channels in pH regulation mechanisms in colorectal cancer cells. It emerged that there is a cross talk among β1-integrins, hERG1, Kca3.1 and sodium-hydrogen exchanger 1 (NHE1) in cells and primary samples of CRCa. So we started to investigate the expression of hERG1, Kca3.1 and NHE1 in breast cancer. For the first time, hERG1 expression was found in primary breast cancer tissues and it emerged that hERG1 expression is associated with molecular subtype group. Since the nNaV1.5 channel has a principle role in breast tumor progression and we found that hERG1 is expressed in breast cancer tissues and in vitro data demonstrated that there is a networking between hERG1 and nNaV1.5 channels, we performed analysis for nNaV1.5. We found that hERG1 and nNaV1.5 are expressed in primary breast cancer samples and they are positively associated. It occured particulary in Basal Like/triple negative samples and the co-expression was found in the some tumor cells. These data encourage us to develop a monoclonal antibody (mAb) capable to recognise the nNaV1.5 channel. Thus 24 mAb clones were produced and screened and we validated putative mAbs and isolated one mAb with promising high specificity for nNaV1.5, with significant oncological therapeutic potential.