title: RNAi screens identify CHD4 as an essential gene in breast cancer growth.
abstract: 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.
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
authors: Carolina
authors: C
authors: D'Alesio
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
authors: Simona
authors: S
authors: Punzi
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
authors: Angelo
authors: A
authors: Cicalese
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
authors: Lorenzo
authors: L
authors: Fornasari
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
authors: Laura
authors: L
authors: Furia
authors: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan 20139, Italy.
authors: Laura
authors: L
authors: Riva
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.|Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Alessandro
authors: A
authors: Carugo
authors: Division of Experimental Therapeutics, European Institute of Oncology, Milan 20141, Italy.
authors: Giuseppe
authors: G
authors: Curigliano
authors: Division of Experimental Therapeutics, European Institute of Oncology, Milan 20141, Italy.
authors: Carmen
authors: C
authors: Criscitiello
authors: School of Medicine, University of Milan, Milan 20122, Italy.|Biobank for Translational Medicine Unit, Department of Pathology, European Institute of Oncology, Milan 20141, Italy.
authors: Giancarlo
authors: G
authors: Pruneri
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.|Department of Oncology, University of Milan, Milan 20139, Italy.
authors: Pier Giuseppe
authors: PG
authors: Pelicci
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
authors: Mario
authors: M
authors: Faretta
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
authors: Daniela
authors: D
authors: Bossi
authors: Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.
authors: Luisa
authors: L
authors: Lanfrancone
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D047368:Tumor Burden
chemical_list: C493956:CDKN1A protein, human; C115323:CHD4 protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; C509277:Mi-2beta protein, mouse; D004265:DNA Helicases
keywords: CHD4; RNAi screen; breast cancer; epigenetic targets; in vivo murine and human models