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bioRxiv · 10.1101/2024.03.11.584461

The Cyclin-Like Protein Spy1 Mediates Tumourigenic Potential of Triple Negative Breast Cancer

Fifield, B.-A.·Pecoraro, C.·Basilious, A.·Gramisteanu, C.·Mailloux, E.·Ferraiuolo, R.-M.·Porter, L. A.
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Abstract

Triple negative breast cancer is an aggressive subtype of breast cancer that relies on systemic chemotherapy as its primary means of treatment. Cell cycle regulators are enriched in drug resistant forms of the disease supporting the potential of targeting cell cycle checkpoints as a therapeutic direction to re-sensitize patients to treatment. Spy1 is an atypical cyclin-like protein that can override cell cycle checkpoints and is elevated in triple negative breast cancer. We report for the first time the effects of CRISPR-Cas9 mediated knockout of Spy1 on functional characteristics of triple negative breast cancer cells and perform unbiased analysis of protein expression to assess global changes in expression which correlate with functional changes in cell properties. Loss of Spy1 reduced rates of proliferation, decreased metastatic potential, and led to a reduction in stemness properties of triple negative breast cancer cells. Importantly, knockout of Spy1 delayed tumour onset in an in vivo model and significantly increased response to chemotherapy, pushing cells towards a senescent state. This data reveals that changes in expression of proteins that are not essential for proliferation and only transiently expressed can have significant impacts on cell dynamics and provides support for targeting the Spy1-CDK2 complex as a new therapeutic avenue in triple negative breast cancer. Statement of SignificanceTargeting the atypical cell cycle regulator Spy1 induces senescence and increases responsiveness of triple negative breast cancer to standard of care chemotherapy.

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Fifield, B.-A., Pecoraro, C., Basilious, A., Gramisteanu, C., Mailloux, E., Ferraiuolo, R.-M., Porter, L. A.. 2024-03-13. The Cyclin-Like Protein Spy1 Mediates Tumourigenic Potential of Triple Negative Breast Cancer. https://doi.org/10.1101/2024.03.11.584461

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