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

Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype, accounting for 8-14% of all cases. While the majority of human ILCs are characterized by the functional loss of E-cadherin (CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation. To identify these genes, we performed a Sleeping Beauty-mediated insertional mutagenesis screen 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/b and Trp53bp2, which are implicated in the regulation of the actin cytoskeleton. Importantly, Myh9, Ppp1r12b and Trp53bp2 are also frequently aberrated in human ILC, highlighting these genes as drivers of a novel oncogenic pathway underlying ILC development.