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YAP transduction drives triple-negative breast cancer aggressiveness through modulating the EGFR‒AKT axis in patient-derived xenograft cells

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Abstract

Aside from the high prevalence of incidents of breast cancer, the high grade of heterogeneity and the dearth of standard treatment guidelines make triple-negative breast cancer (TNBC) the most refractory subtype. Though still in its infancy, the Hippo pathway has been known to play a critical role in tumorigenesis. However, the molecular mechanics through which the pathway exploits the breast cancer (BC) cell vulnerability are largely unexplored. In this study, we observed a relatively higher expression of the Hippo effector, yes-associated protein (YAP), in TNBC patients compared to non-TNBC patients. Thus, we sought to investigate the contribution of Hippo signaling in TNBC by focusing particularly on transducers of the pathway. Impeding YAP transactivation by means of RNA interference or pharmacological inhibition was carried out, followed by evaluation of the subsequent biological changes at the molecular level. We successfully translated the observed data into a TNBC patient-derived xenograft cell line (PDXC). We discovered that nuclear translocation of YAP was associated with TNBC aggressive characteristics and activated the EGFR-AKT axis. Here, we explored the putative role of the Hippo transducer in enhancing cancer hostility and observed that YAP transduction drives proliferation, migration, and survival of TNBC by preventing cellular apoptosis through mediating EGFR activation. These observations suggest that YAP represents a major vulnerability in TNBC cells that may be exploited therapeutically.

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Data availability

All data included in this study will be available from the corresponding author on reasonable request.

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Funding

This work was supported by grant from Department of biotechnology- Government of India (BT/PR1/8812/COE/34/01/2017), and S.T.P received fellowship from Indian council of medical research (2020-7548/CMB-BMS).

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Authors and Affiliations

  1. Laboratory of Molecular Medicine, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, 695011, Kerala, India

    Sulfath Thottungal Parambil, Gisha Rose Antony, Ajeesh Babu Littleflower & Lakshmi Subhadradevi

  2. Division of Cancer Biology, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thiruvananthapuram, 695014, India

    Santhosh Kumar R. Thankayyan

  3. Division of Surgical Oncology, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, 695011, Kerala, India

    Paul Augustine

  4. Division of Pathology, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, 695011, Kerala, India

    Thara Somanathan

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  1. Sulfath Thottungal Parambil
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  2. Santhosh Kumar R. Thankayyan
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  3. Gisha Rose Antony
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  4. Ajeesh Babu Littleflower
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  5. Paul Augustine
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  7. Lakshmi Subhadradevi
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Sulfath Thottungal Parambil, Ajeesh Babu Littleflower, and Gisha Rose Antony. The TNBC-PDXC was developed by Santhosh Kumar T. R. Patient biopsy samples were provided by Paul Augustine, and histopathological analysis was performed by Thara Somanathan. The first draft of the manuscript was written by Sulfath Thottungal Parambil and Lakshmi Subhadradevi, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lakshmi Subhadradevi.

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This study is approved by the Institutional Review Board of Regional Cancer Centre, Trivandrum-India.

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Informed consent was obtained from all the individuals participated in this study.

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Parambil, S.T., Thankayyan, S.R., Antony, G.R. et al. YAP transduction drives triple-negative breast cancer aggressiveness through modulating the EGFR‒AKT axis in patient-derived xenograft cells. Med Oncol 40, 137 (2023). https://doi.org/10.1007/s12032-023-02007-8

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