Trastuzumab-induced HER2 phosphorylation: exploring the mechanisms and implications

Abstract

Cancer is caused by an accumulation of mutations in a stem cell. A defective mismatch repair (MMR) system can lead to such an accumulation of mutations. MMR defects are found in a cancer syndrome called Lynch Syndrome, and tumors of this syndrome are indeed characterized by such an accumulation of mutations, particularly in short repetitive DNA sequences, called microsatellites. When such mutated microsatellites are located in the coding sequences of genes with essential roles for tumorigenesis, we speak of ‘target genes’. Many such target genes have been found and in this review we focus the possible involvement of target genes involved in the estrogen-receptor pathway (ER). We recently identified NRIP1, encoding the nuclear receptor-interacting protein 1, as the most frequently mutated gene in microsatellite instable (MSI) endometrial cancer (EC). NRIP1 is a known corepressor of the ER pathway, the pathway essential in regulating the concentrations of estrogens, a hormone for which the endometrium is highly responsive. This in combination with the fact that high exposure to estrogens is currently considered the major risk factor for EC - approximately 80% of all sporadic EC tumors are estrogen dependent carcinomas - make NRIP1 the perfect target gene for EC. Interestingly, mutations in NRIP1 were also detected in MSI colorectal carcinoma (CRC) samples. Finding mutations in an estrogen receptor signaling protein in colorectal tissue might not be that expected, as colon is not typically associated with being responsive to estrogens. However, evidence is accumulating to better understand this finding. For instance, it was shown that NRIP1, in colon tissue, stimulates APC gene transcription and inhibits β-catenin activation. Moreover, some studies suggested that estrogens can increase the expression of MLH1 in colon cancer cells, highlighting the implications of estrogen protecting against colon cancer, by regulating the MMR system. All in all we conclude that genes involved in the estrogen pathway are the perfect candidates to be studied in MMR-deficient tumors, especially those developing in hormonal responsive tissues.