Crucial and novel cancer drivers in a mouse model of triple-negative breast cancer.

BACKGROUND

We previously developed a mouse model of breast cancer that mimics human triple-negative breast cancer (TNBC) by inactivating the Retinoblastoma (Rb), Transformation related protein 53 (p53), and Breast cancer 1 (Brca1) pathways in the mammary gland. Despite inactivation of all three tumor suppressors throughout the epithelium, low tumor multiplicity indicated that malignant carcinoma progression requires additional oncogenic stimuli.

MATERIALS AND METHODS

In order to identify collaborating genetic events, we performed integrated analysis of 18 tumors (eight tumors with inactivation of pRbf/Brca1/p53 and ten tumors with inactivation of pRbf/p53) using comparative genomic hybridization and global gene expression. We then conducted flow cytometric analysis, immunostaining, tumorsphere, and cell viability assays.

RESULTS

Copy number aberrations were correlated with the transcript levels of 7.55% of genes spanned by the altered genomic regions. Recurrent genomic losses spanning large regions of chromosomes 4 and 10 included several cell death genes. Among the amplified genes were well-known drivers of tumorigenesis including Wingless-related MMTV integration site 2 (Wnt2), as well as potentially novel driver mutations including the Late cornified envelope (LCE) gene family. These tumors have a stem/luminal progenitor phenotype and active β-catenin signaling. Tumorsphere formation and cell survival are suppressed by Wnt pathway inhibitors.

CONCLUSION

Our novel mouse model mimics human TNBC and provides a platform to triage the pathways that underlie malignant tumor progression.