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Nat Genet. 2017 Aug;49(8):1219-1230. doi: 10.1038/ng.3905. Epub 2017 Jun 26.

Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma.

Author information

1
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
3
Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
4
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
5
Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
6
Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
7
Department of EEMCS, Delft University of Technology, Delft, the Netherlands.

Abstract

Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8-14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1. These mice developed multiple independent mammary tumors of which the majority resembled human ILC in terms of morphology and gene expression. Recurrent and mutually exclusive transposon insertions were identified in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, whose products have been implicated in the regulation of the actin cytoskeleton. Notably, MYH9, PPP1R12B and TP53BP2 were also frequently aberrated in human ILC, highlighting these genes as drivers of a novel oncogenic pathway underlying ILC development.

PMID:
28650484
DOI:
10.1038/ng.3905
[Indexed for MEDLINE]

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