Elucidating cooperative genetic events in DCIS progression in mutant <i>p53</i> –driven breast cancer

Ductal carcinoma in situ (DCIS) is a precursor mammary lesion characterized by abnormal epithelial cells in mammary ducts that remain confined to the luminal space. Not all DCIS becomes invasive, and no strategy currently exists in patients to stratify indolent DCIS from DCIS at risk of progression. Several studies of human DCIS and breast cancer suggest that <i>TP53</i> mutations occur early in DCIS. However, <i>TP53</i> mutation alone is insufficient for DCIS formation or transformation to invasive disease. Using an autochthonous somatic mouse model of <i>Trp53^R245W</i> induced breast cancer (equivalent to the <i>TP53^R248W</i> hotspot mutation in humans), we identified DCIS lesions. Through exome sequencing and low-pass whole-genome sequencing, we identified additional genomic changes shared between DCIS and invasive tumors. This comparison nominated seven murine candidate genes, with eight human orthologs. We assessed the cooperativity of these genes with mutant <i>TP53</i> in human breast cells using acinar morphogenesis and migration assays. Overexpression of <i>TMEM267</i>, which encodes a transmembrane protein overexpressed in 22% of <i>TP53</i> missense mutant breast cancer cases, in cells with mutant <i>TP53</i> caused a significant increase in the filled duct, DCIS-like phenotype. We nominate <i>TMEM267</i> as a cooperating event with mutant <i>TP53</i> in DCIS progression.