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

Oncogene volume 39, pages 4592–4602 (2020)Cite this article

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Abstract

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.

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Fig. 1: Mammary epithelial deletion of Slk accelerates Neu-induced tumorigenesis.
Fig. 2: Slk deletion induces Neu-dependent Sox10 expression.
Fig. 3: Slk deletion aberrantly activates PDK1 and AKT.
Fig. 4: Slk deletion increases stem/progenitor activity and tumor growth in an PI3K-dependent manner.
Fig. 5: Sox10 rescues mammary stem/progenitor activity following inhibition of PI3K.
Fig. 6: Sox10 enhances mammary tumor growth and confers resistance to AKT-inhibition in vivo.

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Acknowledgements

KNA-Z and BRP are funded by the Canadian Breast Cancer Foundation. JA-H, JJH, and DPC are funded by scholarships from the Canadian Institutes of Health Research. PR-C is funded by an Ontario Graduate Scholarship. This study was supported by grants from the Canadian Breast Cancer Foundation, the Cancer Research Society, the Canadian Institutes of Health Research and the Canadian Cancer Society Research Institute. This work was also supported in part by a generous donation from Mr Eugene Tassé.

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Authors and Affiliations

  1. Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada

    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

  2. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada

    Khalid N. Al-Zahrani, John Abou-Hamad, David P. Cook, Benjamin R. Pryce, Cédrik Labrèche, Pascale Robineau-Charette, Barbara C. Vanderhyden & Luc A. Sabourin

  3. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, K1H 8M5, Canada

    Jonathan J. Hodgins, John C. Bell, Rebecca C. Auer & Michele Ardolino

  4. Department of Surgery, University of Ottawa, Ottawa, ON, K1H 8M5, Canada

    Rebecca C. Auer

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  1. Khalid N. Al-Zahrani
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Al-Zahrani, K.N., Abou-Hamad, J., Cook, D.P. et al. Loss of the Ste20-like kinase induces a basal/stem-like phenotype in HER2-positive breast cancers. Oncogene 39, 4592–4602 (2020). https://doi.org/10.1038/s41388-020-1315-3

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