Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer

摘要: Triple-negative breast cancer (TNBC), an aggressive disease comprising several subtypes including basal-like and claudin-low, involves frequent deletions or point mutations in TP53, as well loss of PTEN. We previously showed that combined deletion both tumor suppressors the mouse mammary epithelium invariably induced claudin-low-like TNBC. The effect p53 mutation plus Pten on tumorigenesis whether this combination can induce TNBC are unknown. WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H composite mice were generated which is deleted a p53-R270H DNA-binding domain upon expression Cre-recombinase pregnancy-identified alveolar progenitors. Tumors characterized by histology, marker analysis, transcriptional profiling [GEO-GSE75989], bioinformatics, high-throughput (HTP) FDA drug screen orthotopic injection to quantify tumor-initiating cells (TICs) tail vein identify lung metastasis. Combined induction accelerated formation four distinct tumors poorly differentiated adenocarcinoma (PDA) spindle/mesenchymal-like lesions. Transplantation assays revealed highest frequency TICs PDA spindle compared with other subtypes. Hierarchical clustering demonstrated grouped closely human models basal claudin-low subtypes, respectively. HTP screens primary Pten∆:p53∆ vs. Pten∆:p53R270H 1120 FDA-approved drugs identified 8-azaguanine most potent for types, but found no allele-specific inhibitor. A gene set enrichment analysis increased metastasis pathway tumors. Accordingly, following injection, metastases morbidity significantly faster than double-deletion cells, was associated ability upregulate E-cadherin metastases. Our results demonstrate represent tractable model study because unlike deletion, p53R270H does not skew toward subtype. develop enriched TICs, readily form metastasis, provides preclinical immune-competent mice.