Research Papers:

RNAi screens identify CHD4 as an essential gene in breast cancer growth

Carolina D’Alesio, Simona Punzi, Angelo Cicalese, Lorenzo Fornasari, Laura Furia, Laura Riva, Alessandro Carugo, Giuseppe Curigliano, Carmen Criscitiello, Giancarlo Pruneri, Pier Giuseppe Pelicci, Mario Faretta, Daniela Bossi and Luisa Lanfrancone _

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Oncotarget. 2016; 7:80901-80915. https://doi.org/10.18632/oncotarget.12646

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Carolina D’Alesio1,*, Simona Punzi1,*, Angelo Cicalese1, Lorenzo Fornasari1, Laura Furia1, Laura Riva2, Alessandro Carugo1,3, Giuseppe Curigliano4, Carmen Criscitiello4, Giancarlo Pruneri5,6, Pier Giuseppe Pelicci1,7, Mario Faretta1, Daniela Bossi1, Luisa Lanfrancone1

1Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy

2Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan 20139, Italy

3Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA

4Division of Experimental Therapeutics, European Institute of Oncology, Milan 20141, Italy

5School of Medicine, University of Milan, Milan 20122, Italy

6Biobank for Translational Medicine Unit, Department of Pathology, European Institute of Oncology, Milan 20141, Italy

7Department of Oncology, University of Milan, Milan 20139, Italy

*These authors have contributed equally to this work

Correspondence to:

Luisa Lanfrancone, email: [email protected]

Keywords: RNAi screen, epigenetic targets, breast cancer, CHD4, in vivo murine and human models

Received: July 22, 2016    Accepted: September 29, 2016    Published: October 13, 2016


Epigenetic regulation plays an essential role in tumor development and epigenetic modifiers are considered optimal potential druggable candidates. In order to identify new breast cancer vulnerabilities and improve therapeutic chances for patients, we performed in vivo and in vitro shRNA screens in a human breast cancer cell model (MCF10DCIS.com cell line) using epigenetic libraries. Among the genes identified in our screening, we deeply investigated the role of Chromodomain Helicase DNA binding Protein 4 (CHD4) in breast cancer tumorigenesis. CHD4 silencing significantly reduced tumor growth in vivo and proliferation in vitro of MCF10DCIS.com cells. Similarly, in vivo breast cancer growth was decreased in a spontaneous mouse model of breast carcinoma (MMTV-NeuT system) and in metastatic patient-derived xenograft models. Conversely, no reduction in proliferative ability of non-transformed mammary epithelial cells (MCF10A) was detected. Moreover, we showed that CHD4 depletion arrests proliferation by inducing a G0/G1 block of cell cycle associated with up-regulation of CDKN1A (p21). These results highlight the relevance of genetic screens in the identification of tumor frailties and the role of CHD4 as a potential pharmacological target to inhibit breast cancer growth.

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