FRK inhibits breast cancer cell migration and invasion by suppressing epithelial-mesenchymal transition

Abstract

The human fyn-related kinase (FRK) is a non-receptor tyrosine kinase known to have tumor suppressor activity in breast cancer cells. However, its mechanism of action has not been fully characterized. We generated FRK-stable MDA-MB-231 breast cancer cell lines and analyzed the effect on cell proliferation, migration, and invasiveness. We also used kinome analysis to identify potential FRK-regulated signaling pathways. We employed both immunoblotting and RT-PCR to identify/validate FRK-regulated targets (proteins and genes) in these cells. Finally, we interrogated the TCGA and GENT gene expression databases to determine the correlation between the expression of FRK and epithelial/mesenchymal markers. We observed that FRK overexpression suppressed cell proliferation, migration, and invasiveness, inhibited various JAK/STAT, MAPK and Akt signaling pathways, and suppressed the expression of some STAT3 target genes. Also, FRK overexpression increased the expression of epithelial markers including E-cadherin mRNA and down-regulated the transcript levels of vimentin, fibronectin, and slug. Finally, we observed an inverse correlation between FRK expression and mesenchymal markers in a large cohort of breast cancer cells. Our data, therefore, suggests that FRK represses cell proliferation, migration and invasiveness by suppressing epithelial to mesenchymal transition.

BRK Phosphorylates SMAD4 for proteasomal degradation and inhibits tumor suppressor FRK to control SNAIL, SLUG and metastatic potential

“…Interestingly, overexpression of SMAD4 restores the BRK-induced suppression of FRK level in the TNBC cells stably expressing BRK. Previous studies have shown that the expression of SNAIL is upregulated in FRK-knocked down breast cancer cells (30). We observed that activated BRK induces SLUG and SNAIL expression, while overexpression of FRK significantly suppresses the mesenchymal marker SLUG, suggesting an FRK-dependent mechanism for BRK induced promotion of EMT.…”

TRIM44 promotes cell proliferation and migration by inhibiting FRK in renal cell carcinoma

“…Of the 12 genes that were downregulated by TRIM44, three genes were found to possess tumor suppressive functions (Figure A; FRK, EGR1 and BCL2L14 ). We then used the Oncomine dataset to analyze the expression level of these three genes in tumors. FRK was the only gene that showed low expression levels in cancer compared with benign tissues (Figures B,C and ).…”

“…This mutation of the tyrosine residue seemed to prevent the NEDD4‐1 mediated ubiquitination of PTEN . Another study revealed that FRK inhibited cell migration of breast cancer cells through suppressing EMT . FRK is also involved in large cell lymphoma and glioma as a tumor suppressor .…”

“…50 Another study revealed that FRK inhibited cell migration of breast cancer cells through suppressing EMT. 39 FRK is also involved in large cell lymphoma and glioma as a tumor suppressor. 38,[40][41][42] FRK overexpression caused G1 phase arrest that led to apoptosis in glioma cells.…”

“…Of the 12 genes that were downregulated by TRIM44, three genes were found to possess tumor suppressive functions ( Figure 3A; FRK, EGR1 and BCL2L14). [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] We then used the Oncomine dataset to analyze the expression level of these three genes in tumors. FRK was the only gene that showed low We also explored upregulated genes by TRIM44 using the same microarray data ( Figure S3, Table S2).…”