Breast Tumour Kinase (Brk/PTK6) contributes to breast tumour xenograft growth and modulates chemotherapeutic responses in vitro

Burmi, Rajpal S., Box, Gary M., Wazir, Umar, Hussain, Haroon A., Davies, Julie A., Court, William J., Eccles, Suzanne A., Jiang, Wen G. ORCID: https://orcid.org/0000-0002-3283-1111, Mokbel, Kefah and Harvey, Amanda J. 2022. Breast Tumour Kinase (Brk/PTK6) contributes to breast tumour xenograft growth and modulates chemotherapeutic responses in vitro. Genes 13 (3) , 402. 10.3390/genes13030402

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Publisher:	MDPI
ISSN:	2073-4425
Date of First Compliant Deposit:	28 February 2022
Date of Acceptance:	21 February 2022
Last Modified:	08 May 2023 09:24
URI:	https://orca.cardiff.ac.uk/id/eprint/147931

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