In situ quantification of HER2–protein tyrosine kinase 6 (PTK6) protein–protein complexes in paraffin sections from breast cancer tissues

Abstract

Background:Protein tyrosine kinase 6 (PTK6; breast tumour kinase) is overexpressed in up to 86% of the invasive breast cancers, and its association with the oncoprotein human epidermal growth factor receptor 2 (HER2) was shown in vitro by co-precipitation. Furthermore, expression of PTK6 in tumours is linked with the expression of HER2.Method and results:In this study, we used the proximity ligation assay (PLA) technique on formalin-fixed paraffin sections from eighty invasive breast carcinoma tissue specimens to locate PTK6–HER2 protein–protein complexes. Proximity ligation assay signals from protein complexes were assessed quantitatively, and expression levels showed a statistically significant association with tumour size (P=0.015) and course of the cancer disease (P=0.012).Conclusion:Protein tyrosine kinase 6 forms protein complexes with HER2 in primary breast cancer tissues, which can be visualised by use of the PLA technique. Human epidermal growth factor receptor 2–PTK6 complexes are of prognostic relevance.

HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

“…8,9,22,37 Aubele and colleagues reported that high PLA signals, indicating a physical interaction between PTK6 and HER2, correlated with reduced metastasisfree survival, although their earlier findings in 193 invasive breast cancers suggest that PTK6 may be a positive prognostic indicator. 38 This discrepancy has been discussed elsewhere and does highlight the difference between expression at the mRNA level compared with protein-based studies. 8 Additionally, given that the reduction in metastasis free survival with high PTK6 expression appeared to be more marked in the 220 patients with triple-negative or basal-like breast cancer (Fig.…”

Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells

“…Nevertheless, to date, studies that examine and confirm the advantageous effects of simultaneous knockdown of such target pairs are still scarce, although some groups have reported stronger or synergistic effects following the simultaneous knockdown of uPAR and HER2, uPAR and MMP9, or uPA and uPAR (10,35,36). In previous studies, we have shown the association of HER2 with PTK6 in breast cancer (19,20,22). These studies led us to investigate the effects of simultaneous knockdown of HER2 and PTK6.…”

“…Furthermore, the HER2 and PTK6 mRNA and protein levels are positively correlated, emphasizing their role as crucial molecules in breast cancer (17,(20)(21)(22). In 2004, Tanner and colleagues identified a novel HER2-overexpressing cell line that is intrinsically resistant to trastuzumab and named it JIMT-1 (23).…”

PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation

“…Furthermore, PTK6 protein expression in TNBC cells can also be induced by known oncogenic stimuli; for example, hypoxiainducible factor 1a/2a activity promotes PTK6 expression (20). PTK6 localizes to both the cytoplasm and nucleus, and can also be recruited to the cell membrane via interactions with activated growth factor receptors such as IGF-1R and HER2 (22,25,26). PTK6 enhances cell proliferation, migration, growth, and survival via a growing number of interacting proteins and substrates (e.g., Paxillin, STAT3/5, FAK, p130Cas, BKS) and synergy with other oncogenic signaling pathways such as ERK/MAPK and PI3K/AKT (20,22,(27)(28)(29).…”