PLAY IN CONTEXT: EXTRACELLULAR MATRIX RECEPTORS MODULATING HRG SIGNALING IN BREAST CANCER CELLS

TOSCANI, ANDRÉS MARTIN; COLUCCIO LESKOW, FEDERICO

Bariloche

Congreso; SISTAM 2015; 2015

p { margin-bottom: 0.21cm; direction: ltr; color: rgb(0, 0, 10); line-height: 120%; text-align: left; widows: 2; orphans: 2; }p.western { font-family: "Times New Roman",serif; }p.cjk { font-family: "Times New Roman"; }p.ctl { font-family: "Times New Roman"; }a:link { color: rgb(0, 0, 255); } Interaction with the extracellular matrix orchestrates growth and differentiation in several tissues. The Epidermal Growth Factor Receptors (EGFRs) are key players in the signalling repertoire of the mammary gland. Four EGFRs play in tune: EGF can activate both EGFR and erbB4, while erbB3 shows higher affinity for heregulin-beta1 (HRG). ErbB2 has no descripted ligand but exhibits tyrosine kinase activity that can be further enhanced by heterodimerization with EGFR and erbB3 in response to EGF or HRG. Dissonantly, EGFRs are overexpressed in several tumors like prostate, bone, lung and breast, among others. Particularly, erbB2 is a bad prognosis marker in mammary gland tumors. It has been reported that erbB2 interacts with focal adhesion proteins, like beta1-Integrin or FAK, although the relevance of such interaction in both normal and tumoral tissues has not yet been cleared. The aim of the present work is to characterize both physical and functional interactions between erbB family receptors, particularly erbB2, and extracellular matrix receptors. In order to evaluate the modulation of HRG response by the extracellular matrix, we measured AKT activation in MCF7 cells growing on different substrates. Our results show an attenuation HRG signaling on cells growing on Collagen as compare to Fibronectin. In contrast with previous reports, no evidence of erbB2 clusters and beta1-integrin was observed in MCF7 cells. We could only find colocalization between these receptors outside focal adhesion complexes in cells overexpressing both proteins, suggesting an interaction between resting receptors. Discoidin Domain Receptor 1 (DDR1) is a tyrosine kinase receptor which recognize several types of Collagen and is broadly expressed, particularly in both normal and tumoral mammary gland cells. We have found that DDR1 coimmunoprecipitates and colocalizes with erbB2, suggesting its role as a modulator of HRG response in MCF7 cells. These experiments suggest a central role for DDR1 mediating extracellular matrix regulation of growth factor receptors. Additionally, we showed that these are multidimensional processes in which many factors, including expression levels of receptors, the nature of the substrate and concentration of growth factors, regulate the signaling processes responsible of the determination of cell fate.