The potential and role of breast tumour kinase(Brk) isoforms in breast cancer therapeutics

Abstract

Breast tumour kinase (Brk)/PTK6 is over-expressed in 80% of all breast cancers and has shown to be involved in tumour development and progression of breast cancer. There is a lack of development of breast tumour kinase (Brk) inhibitors and, therefore the clinical benefits associated with Brk inhibition are unknown. Due to Brk’s known role in proliferation and cell death, it was hypothesised that it may modulate responses to common breast cancer therapies. ALT-PTK6 is an alternatively spliced isoform of Brk and may act as a competitive inhibitor of the full-length form. Little is known regarding ALT-PTK6’s role in breast cancer therapeutics. I hypothesised ALT-PTK6 may negatively regulate cell proliferation within breast cancer cell lines and thus reduce the oncogenic functions of the full-length form. Initially, in vitro studies using multiple breast cancer cell showed survival at 2Gy radiation dose (SF2) correlated with Brk expression levels for some cell lines, with high SF2 survival there was also higher Brk expression. DNA repair kinetics and Brk interaction with ataxia telangiectasia mutated protein (ATM) showed no significant differences in relation to Brk expression. Brk modulates response to: Paclitaxel (Taxol), Doxorubicin, Lapatinib, Tamoxifen and showed significant reduction in cell proliferation in combination with a novel Brk inhibitor (Compound 4f) suggesting potential for a Brk targeted therapy. It was hypothesised that due to the proposed role of ALT-PTK6 as a negative regulator of Brk, ALT-PTK6/PTK6 transcript ratios will be lower in breast cancer cells and tissues. There were increased ALT-PTK6 to PTK6 transcript ratios in non-cancerous cell lines, hormone (ER/PR) positive and HER2 positive breast cancer cell lines compared to hormone negative cell lines. ALT-PTK6/PTK6 ratioswere increased in patients with improved overall survival. Thus, there is potential for ALT-PTK6/PTK6 ratios as a prognostic factor for long term overall survival in breast cancer patients.