2. Academic Validation
  3. WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells

WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells

  • Breast Cancer Res. 2019 Nov 21;21(1):123. doi: 10.1186/s13058-019-1216-y.
Simona Punzi 1,  Chiara Balestrieri 1 2 3,  Carolina D'Alesio 1 4,  Daniela Bossi 1 5,  Gaetano Ivan Dellino 1 6,  Elena Gatti 1,  Giancarlo Pruneri 6 7 8,  Carmen Criscitiello 6 9,  Giulia Lovati 1,  Marine Meliksetyan 1,  Alessandro Carugo 10,  Giuseppe Curigliano 6 9,  Gioacchino Natoli 1 2 3,  Pier Giuseppe Pelicci 1 6,  Luisa Lanfrancone 11
Affiliations

Affiliations

  • 1 Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy.
  • 2 Humanitas University, Pieve Emanuele (MI), 20090, Italy.
  • 3 Humanitas Clinical and Research Institute, Rozzano (MI), 20089, Italy.
  • 4 Present address: Department of Internal Medicine and Medical Specialties (Di.M.I), University of Genova, Genoa, Italy.
  • 5 Present address: Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • 6 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
  • 7 Department of Pathology, Biobank for Translational Medicine Unit, European Institute of Oncology, IRCCS, Milan, Italy.
  • 8 Present address: Istituto Nazionale dei Tumori - Fondazione IRCCS, Milan, Italy.
  • 9 Division of Early Drug Development for Innovative Therapy, European Institute of Oncology IRCCS, Milan, Italy.
  • 10 Institute for Applied Cancer Science, UT MD Anderson Cancer Cente, Houston, TX, 77030, USA.
  • 11 Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy. [email protected].
PMID: 31752957 DOI: 10.1186/s13058-019-1216-y
Abstract

Background: Development of metastases and drug resistance are still a challenge for a successful systemic treatment in breast Cancer (BC) patients. One of the mechanisms that confer metastatic properties to the cell relies in the epithelial-to-mesenchymal transition (EMT). Moreover, both EMT and metastasis are partly modulated through epigenetic mechanisms, by repression or induction of specific related genes.

Methods: We applied shRNAs and drug targeting approaches in BC cell lines and metastatic patient-derived xenograft (PDX) models to inhibit WDR5, the core subunit of histone H3 K4 methyltransferase complexes, and evaluate its role in metastasis regulation.

Result: We report that WDR5 is crucial in regulating tumorigenesis and metastasis spreading during BC progression. In particular, WDR5 loss reduces the metastatic properties of the cells by reverting the mesenchymal phenotype of triple negative- and luminal B-derived cells, thus inducing an epithelial trait. We also suggest that this regulation is mediated by TGFβ1, implying a prominent role of WDR5 in driving EMT through TGFβ1 activation. Moreover, such EMT reversion can be induced by drug targeting of WDR5 as well, leading to BC cell sensitization to chemotherapy and enhancement of paclitaxel-dependent effects.

Conclusions: We suggest that WDR5 inhibition could be a promising pharmacologic approach to reduce cell migration, revert EMT, and block metastasis formation in BC, thus overcoming resistance to standard treatments.

Keywords

Breast cancer; EMT; Metastasis; TGFβ1; WDR5.

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