Loss of the Ste20-like kinase induces a basal/stem-like phenotype in HER2-positive breast cancers.

Oncogene 2020 Jun

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HER2 is overexpressed in 20-30% of all breast cancers and is associated with an invasive disease and poor clinical outcome. The Ste20-like kinase (SLK) is activated downstream of HER2/Neu and is required for efficient epithelial-to-mesenchymal transition, cell cycle progression, and migration in the mammary epithelium. Here we show that loss of SLK in a murine model of HER2/Neu-positive breast cancers significantly accelerates tumor onset and decreases overall survival. Transcriptional profiling of SLK knockout HER2/Neu-derived tumor cells revealed a strong induction in the triple-negative breast cancer marker, Sox10, accompanied by an increase in mammary stem/progenitor activity. Similarly, we demonstrate that SLK and Sox10 expression are inversely correlated in patient samples, with the loss of SLK and acquisition of Sox10 marking the triple-negative subtype. Furthermore, pharmacological inhibition of AKT reduces SLK-null tumor growth in vivo and is rescued by ectopic Sox10 expression, suggesting that Sox10 is a critical regulator of tumor growth downstream of SLK/AKT. These findings highlight a role for SLK in negatively regulating HER2-induced mammary tumorigenesis and provide mechanistic insight into the regulation of Sox10 expression in breast cancer.

Citation

Khalid N Al-Zahrani, John Abou-Hamad, David P Cook, Benjamin R Pryce, Jonathan J Hodgins, Cédrik Labrèche, Pascale Robineau-Charette, Christiano T de Souza, John C Bell, Rebecca C Auer, Michele Ardolino, Barbara C Vanderhyden, Luc A Sabourin. Loss of the Ste20-like kinase induces a basal/stem-like phenotype in HER2-positive breast cancers. Oncogene. 2020 Jun;39(23):4592-4602