Breast Tumour Kinase (Brk/PTK6) Contributes to Breast Tumour Xenograft Growth and Modulates Chemotherapeutic Responses In Vitro.

Rajpal S Burmi,Suzanne A Eccles,Amanda J Harvey,William J Court,Gary M Box,Kefah Mokbel,Julie A Davies,Umar Wazir,Wen G Jiang,Haroon A Hussain

doi:10.3390/genes13030402

Abstract

Breast tumour kinase (Brk/PTK6) is overexpressed in up to 86% of breast cancers and is associated with poorer patient outcomes. It is considered a potential therapeutic target in breast cancer, even though the full spectrum of its kinase activity is not known. This study investigated the role of the kinase domain in promoting tumour growth and its potential in sensitising triple negative breast cancer cells to standard of care chemotherapy. Triple negative human xenograft models revealed that both kinase-inactive and wild-type Brk promoted xenograft growth. Suppression of Brk activity in cells subsequently co-treated with the chemotherapy agents doxorubicin or paclitaxel resulted in an increased cell sensitivity to these agents. In triple negative breast cancer cell lines, the inhibition of Brk kinase activity augmented the effects of doxorubicin or paclitaxel. High expression of the alternatively spliced isoform, ALT-PTK6, resulted in improved patient outcomes. Our study is the first to show a role for kinase-inactive Brk in human breast tumour xenograft growth; therefore, it is unlikely that kinase inhibition of Brk, in isolation, would halt tumour growth in vivo. Breast cancer cell responses to chemotherapy in vitro were kinase-dependent, indicating that treatment with kinase inhibitors could be a fruitful avenue for combinatorial treatment. Of particular prognostic value is the ratio of ALT-PTK6:Brk expression in predicating patient outcomes.

Highlights

Breast tumour kinase, known as protein tyrosine kinase 6 (Brk/PTK6) is overexpressed in a high proportion of invasive breast cancers, and represents a possible target for therapeutic intervention [1,2]
In vitro studies have shown that by expression of ptk6 (Brk) expression increases breast cancer cell proliferation [3], migration [4,5,6], and protects the cells from the induction of autophagic and apoptotic cell death [1,7]
One of the initial aims of this study was to examine the potential of Brk to promote breast tumour growth, independent of exogenous influences such as HER2 expression, to eliminate the effect of HER2 in tumour growth, as most Brk expressing tumours are HER2 negative, and to establish whether the kinase function of Brk was required

Summary

Introduction

Known as protein tyrosine kinase 6 (Brk/PTK6) is overexpressed in a high proportion of invasive breast cancers, and represents a possible target for therapeutic intervention [1,2]. In vitro studies have shown that Brk expression increases breast cancer cell proliferation [3], migration [4,5,6], and protects the cells from the induction of autophagic and apoptotic cell death [1,7]. Brk involvement in regulating ErbB (erythroblastic leukemia viral oncogene B) receptor signaling is its most well-described role in breast tumorigenesis. MAPK, and ARAP-1 have all been attributed to Brk activity in response to ErbB ligands, resulting in increased cell proliferation, cell cycle progression, and migration [2,11,12,13,14]. Brk regulates processes involved in breast cancer progression in response to non-ErbB receptor ligands such as HGF, OPN, and IGF [6,7,15]. Research avenues away from unravelling Brk signaling have focussed on Brk effects in tumour development and treatment

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