Fish Expression as a Biomarker for Cell Invasion
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The non-receptor tyrosine kinase and potent proto-oncogene, Src, is known to have elevated expression and/or increased activity in a very high percentage of breast cancers (Courtneidge 2002). Fish is a scaffolding protein and Src substrate. It contains an amino-terminal phox homology (PX) domain, five Src homology 3 (SH3) domains, as well as multiple motifs for binding both SH2 and SH3 domain-containing proteins. Interestingly, Fish localizes to actin-rich structures called podosomes, also known as invadopodia (Chen and Wang 1999). The critical observations that podosomes; have only been found in motile cells, regulate the activity of matrix metalloproteases, and are involved in cytoskeleton degradation and remodeling, implicate these structures in invasive cell migration . Such aggressive cell invasion is implicated in the metastatic potential of human breast tumors. Recent findings in our lab suggest that Fish may serve as an adaptor molecule allowing Src to impinge on growth factor processing and cell adhesion, and motility (data not shown). Since Fish seems to play a role in the formation and activity of podosomes which may mediate cell invasion investigation of this protein is critical in providing insight into future drug therapy designs that will allow for early diagnosis of potentially metastatic tumors. To evaluate the role of Fish as a biomarker for cell invasion in the progression of tumors, we developed and optimized a Fish assay for paraffin-embedded tissue specimens. Using immunohistochemical techniques, levels of Fish expression were analyzed in both invasive and non-invasive cancer cell lines. Consistent with our hypothesis that Fish expression is positively correlated with more aggressive stages of the disease, we found that levels of Fish expression in carcinoma samples compare, respectively, to invasiveness of the cell lines tested.