WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-11-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13058-019-1216-y |
| _version_ | 1818661877184462848 |
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| author | Simona Punzi Chiara Balestrieri Carolina D’Alesio Daniela Bossi Gaetano Ivan Dellino Elena Gatti Giancarlo Pruneri Carmen Criscitiello Giulia Lovati Marine Meliksetyan Alessandro Carugo Giuseppe Curigliano Gioacchino Natoli Pier Giuseppe Pelicci Luisa Lanfrancone |
| author_facet | Simona Punzi Chiara Balestrieri Carolina D’Alesio Daniela Bossi Gaetano Ivan Dellino Elena Gatti Giancarlo Pruneri Carmen Criscitiello Giulia Lovati Marine Meliksetyan Alessandro Carugo Giuseppe Curigliano Gioacchino Natoli Pier Giuseppe Pelicci Luisa Lanfrancone |
| author_sort | Simona Punzi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T04:52:02Z |
| format | Article |
| id | doaj.art-75b0b17024314c6dacd446b155f5075f |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-17T04:52:02Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-75b0b17024314c6dacd446b155f5075f2022-12-21T22:02:52ZengBMCBreast Cancer Research1465-542X2019-11-0121111810.1186/s13058-019-1216-yWDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cellsSimona Punzi0Chiara Balestrieri1Carolina D’Alesio2Daniela Bossi3Gaetano Ivan Dellino4Elena Gatti5Giancarlo Pruneri6Carmen Criscitiello7Giulia Lovati8Marine Meliksetyan9Alessandro Carugo10Giuseppe Curigliano11Gioacchino Natoli12Pier Giuseppe Pelicci13Luisa Lanfrancone14Department of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Oncology and Hemato-Oncology, University of MilanDepartment of Oncology and Hemato-Oncology, University of MilanDepartment of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Experimental Oncology, European Institute of Oncology IRCCSInstitute for Applied Cancer Science, UT MD Anderson Cancer CenteDepartment of Oncology and Hemato-Oncology, University of MilanDepartment of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Experimental Oncology, European Institute of Oncology IRCCSAbstract 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.http://link.springer.com/article/10.1186/s13058-019-1216-yBreast cancerEMTMetastasisTGFβ1WDR5 |
| spellingShingle | Simona Punzi Chiara Balestrieri Carolina D’Alesio Daniela Bossi Gaetano Ivan Dellino Elena Gatti Giancarlo Pruneri Carmen Criscitiello Giulia Lovati Marine Meliksetyan Alessandro Carugo Giuseppe Curigliano Gioacchino Natoli Pier Giuseppe Pelicci Luisa Lanfrancone WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells Breast Cancer Research Breast cancer EMT Metastasis TGFβ1 WDR5 |
| title | WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells |
| title_full | WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells |
| title_fullStr | WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells |
| title_full_unstemmed | WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells |
| title_short | WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells |
| title_sort | wdr5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells |
| topic | Breast cancer EMT Metastasis TGFβ1 WDR5 |
| url | http://link.springer.com/article/10.1186/s13058-019-1216-y |
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