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

Genes

卷:13

Wen G. Jiang¹  Rajpal S. Burmi²  Julie A. Davies²  Amanda J. Harvey²  Haroon A. Hussain²  Gary M. Box³  Suzanne A. Eccles³  William J. Court³  Umar Wazir⁴  Kefah Mokbel⁴ 

[1] Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK;

[2] Centre for Genome Engineering and Maintenance, Institute for Health Medicine and Environments, Brunel University London, Uxbridge UB8 3PH, UK;

[3] The Cancer Research UK Cancer Therapeutics Unit, McElwain Laboratories, The Institute of Cancer Research, Sutton SM2 5NG, UK;

[4] The London Breast Institute, Princess Grace Hospital, London W1U 5NY, UK;

关键词: Brk/PTK6;    ALT-PTK6;    breast cancer;    chemotherapy;    kinase;    prognosis;   

DOI  :  10.3390/genes13030402

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown