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Cytokeratin 5 alters β-catenin dynamics in breast cancer cells

Oncogene volume 39, pages 2478–2492 (2020)Cite this article

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Abstract

Estrogen receptor (ER) positive breast cancers often contain subpopulations of cells that express the intermediate filament protein cytokeratin 5 (CK5). CK5+ cells are enriched in cancer stem cell (CSC) properties, can be induced by progestins, and predict poor prognosis in ER+ breast cancer. We established through CK5 knockout and overexpression in ER+ breast cancer cell lines that CK5 is important for tumorsphere formation, prompting us to speculate that CK5 has regulatory activity in CSCs. To interrogate CK5 interacting proteins that may be functionally cooperative, we performed immunoprecipitation-mass spectrometry for CK5 in ER+ breast cancer cells. Focusing on proteins with signaling activity, we identified β-catenin, a key transcription factor of the Wnt signaling pathway and cell adhesion molecule, as a CK5 interactor, which we confirmed by co-immunoprecipitation in several breast cancer models. We interrogated the dual functions of β-catenin in relation to CK5. Knockout or knockdown of CK5 ablated β-catenin transcriptional activity in response to progestins and Wnt stimuli. Conversely, CK5 induced by progestins or overexpression was sufficient to promote the loss of β-catenin at the cell membrane and total E-cadherin loss. A breast cancer patient-derived xenograft showed similar loss of membrane β-catenin and E-cadherin in CK5+ but not intratumoral CK5− cells and single-cell RNA sequencing found the top enriched pathways in the CK5+ cell cluster were cell junction remodeling and signaling. This report highlights that CK5 actively remodels cell morphology and that blockade of CK5-β-catenin interaction may reverse the detrimental properties of CK5+ breast cancer cells.

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Fig. 1: CK5 is required for progestin induced and sufficient for de novo tumorsphere formation in ER+ breast cancer cells.
Fig. 2: CK5 interacts with β-catenin in luminal and basal breast cancer cells.
Fig. 3: CK5 enhances β-catenin transcriptional activity.
Fig. 4: CK5 promotes loss of β-catenin at the cell membrane.
Fig. 5: CK5+ cells lose E-cadherin.
Fig. 6: CK5+ cells in an ER+ patient-derived tumor model have altered adherens junctions.
Fig. 7: Proposed model of CK5 remodeling of ER+ breast cancer cells.

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Acknowledgements

We thank the University of Colorado School of Medicine Biological Mass Spectrometry Facility and Advanced Light Microscopy Core for their assistance. This work was supported by National Institutes of Health grants NIH F31 CA232456 (OM), NIH 2R01 CA140985 (CAS), and the Breast Cancer Research Foundation (CAS).

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  1. Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Olivia McGinn, Ashley V. Ward, Lynsey M. Fettig, Duncan Riley, Joshua Ivie, Jessica Finlay-Schultz & Carol A. Sartorius

  2. Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Kiran V. Paul & Peter Kabos

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McGinn, O., Ward, A.V., Fettig, L.M. et al. Cytokeratin 5 alters β-catenin dynamics in breast cancer cells. Oncogene 39, 2478–2492 (2020). https://doi.org/10.1038/s41388-020-1164-0

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