Cross-talk between ER and HER2 in breast carcinoma

Abstract

In tumors in which estrogen receptor (ER) and growth factor signaling pathways are simultaneously active, there is a bidirectional cross-talk that results in a positive feedback cycle of cell survival and proliferation stimuli. Beside the postulated inverse correlation between ER and HER2 (human epidermal growth factor receptor 2) as a consequence of repressive feedback signaling loop, there are also other mechanisms regarding ER-HER2 interactions. It seems that MAPK (mitogen-activated protein kinase) pathway has a central role in synergistic action between ER and HER2 in normal mammary gland development, as well in the breast cancer. MAPK pathway is hyperstimulated in cells that overexpress HER2 as a consequence of HER2 gene amplification. In ER+ tumors, MAPK phosphorylates and activates either ER itself or ER coregulators, enhancing the transcriptional activation potential of ER. ER and HER2 signaling could interact on multiple levels (genomic or non-genomic) and therefore might induce reduced ER expression or might increase ER function. Based on our own research, dominant effect of postulated cross-talk was not related to HER2-induced reduced expression of ER (no difference in quantitative levels of ER in ER+ tumors regarding their HER2 status and no difference in progression-free time between ER+HER2- and ER+HER2+ patients) as presented. The importance of understanding ER-HER2 cross-talk is not only because of its significance in breast cancer progression, but because it seems to be fundamental factor in endocrine resistance that can improve treatment strategies, especially targeting MAPK pathway. .