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WDR5 regulates epithelial-to-mesenchymal transition in breast cancer cells via TGFβ

View ORCID ProfilePunzi Simona, Balestrieri Chiara, D’Alesio Carolina, Bossi Daniela, Dellino Gaetano Ivan, Gatti Elena, Pruneri Giancarlo, Criscitiello Carmen, Carugo Alessandro, Curigliano Giuseppe, Natoli Gioacchino, Pelicci Pier Giuseppe, Lanfrancone Luisa
doi: https://doi.org/10.1101/348532
Punzi Simona
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
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  • ORCID record for Punzi Simona
Balestrieri Chiara
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
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D’Alesio Carolina
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
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Bossi Daniela
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
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Dellino Gaetano Ivan
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
2Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Gatti Elena
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
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Pruneri Giancarlo
3School of Medicine, University of Milan, 20122 Milan, Italy
4Biobank for Translational Medicine Unit, Department of Pathology, European Institute of Oncology, Milan 20141, Italy
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Criscitiello Carmen
5Division of Early Drug Development for Innovative Therapy, University of Milano, European Institute of Oncology, Milan, Italy
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Carugo Alessandro
6Institute for Applied Cancer Science, UT MD Anderson Cancer Center, Houston, TX 77030, USA
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Curigliano Giuseppe
5Division of Early Drug Development for Innovative Therapy, University of Milano, European Institute of Oncology, Milan, Italy
7Department of Oncology and Hemato-Oncology, University of Milano, European Institute of Oncology, Milan, Italy
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Natoli Gioacchino
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
8Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
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Pelicci Pier Giuseppe
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
9Department of Oncology, University of Milan, Milan, Italy
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Lanfrancone Luisa
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
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  • For correspondence: luisa.lanfrancone@ieo.it
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Abstract

Even if the mortality rate in breast cancer (BC) has recently decreased, development of metastases and drug resistance are still challenges to successful systemic treatment. The epithelial-to-mesenchymal transition (EMT), as well as epigenetic dynamic modifications, plays a pivotal role in invasion, metastasis, and drug resistance. Here, we report that WDR5, the core subunit of histone H3 K4 methyltransferase complexes, is crucial in coordinating EMT and regulating epigenetic changes that drive metastasis. We show that silencing of WDR5 in BC up-regulates an epithelial signature in triple negative and luminal B like patients by transcriptional repression of mesenchymal genes and reduction of the metastatic properties of these cells. Moreover, we demonstrate that this regulation is mediated by inhibition of the TGFβ signaling both at the transcriptional and post-translational level, suggesting an active role of WDR5 in guiding tumor plasticity upon oncogenic insults, regardless of the pathological BC subtypes.

We therefore suggest that WDR5 inhibition could be a successful pharmacologic approach to inhibit EMT and sensitize breast cancer cells to chemotherapy.

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Posted June 16, 2018.
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WDR5 regulates epithelial-to-mesenchymal transition in breast cancer cells via TGFβ
Punzi Simona, Balestrieri Chiara, D’Alesio Carolina, Bossi Daniela, Dellino Gaetano Ivan, Gatti Elena, Pruneri Giancarlo, Criscitiello Carmen, Carugo Alessandro, Curigliano Giuseppe, Natoli Gioacchino, Pelicci Pier Giuseppe, Lanfrancone Luisa
bioRxiv 348532; doi: https://doi.org/10.1101/348532
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WDR5 regulates epithelial-to-mesenchymal transition in breast cancer cells via TGFβ
Punzi Simona, Balestrieri Chiara, D’Alesio Carolina, Bossi Daniela, Dellino Gaetano Ivan, Gatti Elena, Pruneri Giancarlo, Criscitiello Carmen, Carugo Alessandro, Curigliano Giuseppe, Natoli Gioacchino, Pelicci Pier Giuseppe, Lanfrancone Luisa
bioRxiv 348532; doi: https://doi.org/10.1101/348532

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