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

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.

Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer

“…In addition to their roles in EMT and CSCs (discussed above), RUNX factors have been implicated in ER signaling. Loss of function mutations in the DNA binding‐Runt homology domain of RUNX1 were detected with a particular frequency in the luminal A ER+ subtype of breast cancer (Figure ). Mechanistically, RUNX1 has been shown to recruit and tether ERα to the genome in breast cancer .…”

Mouse models in the era of large human tumour sequencing studies

“…CRISPR-based screening approaches are less amenable to studying dosage-dependent effects as genes are inactivated rather than transcriptionally suppressed, although dosage reduction can be achieved if Cas9 only induces heterozygous loss of the gene, as we have previously observed for in vivo validation of candidates from a Sleeping Beauty IM screen [93]. With the development of new technologies, CRISPR-based screening approaches are extending beyond loss-of-function screens by enabling gene activation using CRISPRa [121], gene inhibition using CRISPRi [122] and the introduction of point mutations with dCas9-AID or dCas9-APOBEC base editors [60,61].…”

Scinderin‑knockdown inhibits proliferation and promotes apoptosis in human breast carcinoma cells

“…n None/low, n (%) High, n (%) to BC (25)(26)(27). SCIN contains six gelsolin-like domains, three actin-binding sites and two calcium-binding sites (6,28).…”