BRK confers tamoxifen-resistance in breast cancer via regulation of tyrosine phosphorylation of CDK1.

Abstract

Tamoxifen (Tam) has been the first-line therapy for estrogen receptor-positive breast cancer since its FDA-approval in 1998. Tam-resistance, however, presents a challenge and the mechanisms that drive it have yet to be fully elucidated. The non-receptor tyrosine kinase BRK/PTK6 is a promising candidate as previous research has shown that BRK knockdown resensitizes Tam-resistant breast cancer cells to the drug. However, the specific mechanisms that drive its importance to resistance remain to be investigated. Here, we investigate the role and mechanism of action of BRK in Tam-resistant (TamR), ER+, and T47D breast cancer cells using phosphopeptide enrichment and high throughput phopshoproteomics analysis. We conducted BRK-specific shRNA knockdown in TamR T47D cells and compared phosphopeptides identified in these cells with their Tam-resistant counterpart and parental, Tam-sensitive cells (Par). A total of 6492 STY phosphosites were identified. Of these sites, 3739 high-confidence pST sites and 118 high-confidence pY sites were analyzed for significant changes in phosphorylation levels to identify pathways that were differentially regulated in TamR versus Par and to investigate changes in these pathways when BRK is knocked down in TamR. We observed and validated increased CDK1 phosphorylation at Y15 in TamR cells compared to BRK-depleted TamR cells. Our data suggest that BRK is a potential Y15-directed CDK1 regulatory kinase in Tam-resistant breast cancer.

• Authors: Aditya Mandapati, Zhibin Ning, Akanksha Baharani, Kiven Erique Lukong
• Journal: Cellular signalling (Cell Signal) Vol. 108 Pg. 110723 (08 2023) ISSN: 1873-3913 [Electronic] England
• PMID: 37216999 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier Inc.

Chemical References

• CDC2 Protein Kinase
• CDK1 protein, human
• Tamoxifen
• Tyrosine
• PTK6 protein, human
• Protein-Tyrosine Kinases

Topics

• Female
• Humans
• Breast Neoplasms (metabolism)
• CDC2 Protein Kinase (metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Phosphorylation
• Signal Transduction
• Tamoxifen (therapeutic use)
• Tyrosine (metabolism)
• Protein-Tyrosine Kinases (metabolism)