Prognostic value of protein tyrosine kinase 6 (PTK6) for long-term survival of breast cancer patients

Abstract

The cytoplasmic tyrosine kinase PTK6 (BRK) shows elevated expression in approximately two-thirds of primary breast tumours, and is implicated in EGF receptor-dependent signalling and epithelial tumorigenesis. Using immunohistochemistry, we performed a retrospective study on 426 archival breast cancer samples from patients with long-term follow-up and compared the protein expression levels of PTK6, the HER receptors, Sam68 (a substrate of PTK6), and signalling proteins including MAP kinase (MAPK), phosphorylated MAPK (P-MAPK), and PTEN. We show that PTK6 expression is of significant prognostic value in the outcome of breast carcinomas. In multivariate analysis, the disease-free survival of patients of X240 months was directly associated with the protein expression level of PTK6 (Pp0.001), but was also inversely associated with nodal status (Pp0.001) and tumour size (Pp0.01). PTK6 expression in tumour tissue significantly correlated (Pp0.05) with the expression of PTEN, MAPK, P-MAPK, and Sam68. To investigate whether these correlations may be due to molecular interactions between PTK6 and these proteins, we used protein extracts from the T47D cell line for immunoprecipitation and western blot analysis. By this, interactions could be demonstrated between PTK6 and MAPK, P-MAPK, HER2/neu, HER3, HER4, PTEN, and Sam68. On the basis of these results, we suggest that PTK6 may serve as a future target for the development of novel treatments in breast cancer.

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

“…PTK6 was also shown to be expressed in several cancer cell lines (11)(12)(13). In the last decade, we and others have identified several interaction partners of PTK6, such as STAT3, (p38) MAPK, Paxillin, and PTEN (14)(15)(16)(17). Therefore, PTK6 seems to be involved in several cellular processes, such as proliferation, migration and invasion.…”

“…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).…”

Evolution of breast cancer therapeutics: Breast tumour kinase’s role in breast cancer and hope for breast tumour kinase targeted therapy

“…Coexpression of Brk and HER2 has been linked to co-amplification of both the ErbB2 and ptk6 genes [35] , although this is not a consistent finding in other patient studies. It is worth noting that although HER2 is over expressed in 20%-30% of breast cancers [44] , Brk is over expressed in upto 86% of breast cancers [47] , which indicates that in the majority of breast cancers Brk is over expressed independently of HER2 status.…”

Future Therapeutic Strategies: Implications for Brk Targeting

“…Without cellular targeting via an NLS or myristoylation, Brk's cellular localization is not tightly regulated; as a result, we now know that it can be found localized in different cellular compartments based on its protein-protein interactions. It has been reported at the membrane via association with ErbB growth factor receptors and the adamalysin ADAM15 (Zhong et al, 2008), in the cytoplasm interacting with paxillin and mitogen activated protein (MAP) kinase (Aubele et al, 2008;Chen et al, 2004) as well as in the nucleus through interactions with RNA binding proteins such as Src-associated in mitosis-68 (Sam68) and the Sam68-like mammalian proteins, SLM1 and SLM2 (Derry et al, 2000;Haegebarth et al, 2004). In normal human prostate epithelial cells and welldifferentiated prostate carcinomas, Brk was localized in the nucleus whereas poorly differentiated prostate tumours had cytoplasmic Brk (Derry et al, 2003).…”

“…For example, the importance of ErbB signalling in breast tumour progression has been well-documented (reviewed in Navolanic et al, 2003) and clinical inhibition of this pathway with therapies such as trastuzumab and lapatinib is now routine for relevant sub-types of breast cancer (CRUK website). Brk associates with all 4 members of the ErbB receptor family (Aubele et al, 2008;Kamalati et al, 1996; and therefore is capable of promoting downstream signalling in response to ErbB ligand binding. Brk also attenuates EGFR signalling through interaction with and phosphorylation of ARAP1 (also known as Arf-GAP, Rho-GAP, ankyrin repeat, and pleckstrin homology (PH) domaincontaining protein 1) (Kang et al, 2010), as well as regulating possibly regulating signalling via reported interactions with PTEN and Akt (Aubele et al, 2008;Zhang et al, 2005).…”