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Src functionality in breast cancer: contribution of the adapters and catalytic domains

The Src family kinases (SFKs) were the first described oncogenic and proto-oncogenic group of non-receptor family of tyrosine kinases. The structure of the SFKs is modular, and not only shows tyrosine kinase domain, but also contributes to define the concept of adapter/docking functional domains of proteins. It contains the Src Homology Domains 2 and 3 (SH2 and SH3), allowing the Src kinases to interact with other proteins in order to form signaling complexes. There are nine members in SFKs (c-Src, Blk, Fyn, Fgr, Hck, Lck, Lyn, Yes y Ykr), three of them, c-Src, Fyn and Yes, are ubiquitously expressed, while the others have a more specific cell type expression.

The proto-oncogene c-Src is required for cellular homeostasis; its hyper-activation/expression is associated with tumor progression and metastasis in humans (breast, pancreas, colon, ovary, lung, etc.); however, the molecular mechanisms are not completely defined. Most of c-Src studies have concentrated on its catalytic activity, and several inhibitors were designed for clinical practice. Some groups, including ours, have shown that c-Src SH2/SH3 adapter domains are necessary for its full functionality. In breast cancer, Triple Negative Tumors (negative for estrogen and progesterone receptors, and for HER2 overexpression) are highly metastatic, and do not have effective therapeutic targets; in these tumors, hyper-activation of c-Src predisposes for bone metastases. In metastatic cells, c-Src controls proliferation, migration, and invasion. Moreover, c-Src is involved in the regulation of secretion and protein composition of the secretome (metalloproteases, etc.) and the exosomes (Cyr61, LOXL2, etc.); in this way c-Src influences the microenvironment for the primary tumor and the metastatic niche. Our working hypothesis postulates that the SH2/SH3 adapter domains are essential for c-Src full functionality in breast cancer metastasis. We aim to study in the human metastatic triple negative cell lines MDA-MB-231 and SUM159PT, the functionality of the adapter and catalytic domains of c-Src.