RT Journal Article
SR Electronic
T1 Crucial and Novel Cancer Drivers in a Mouse Model of Triple-negative Breast Cancer
JF Cancer Genomics - Proteomics
JO Cancer Genomics Proteomics
FD International Institute of Anticancer Research
SP 115
OP 126
VO 11
IS 3
A1 JACOB P. S. JOHNSON
A1 PRASHANT KUMAR
A1 MIROSLAV KOULNIS
A1 MILAN PATEL
A1 KARL SIMIN
YR 2014
UL http://cgp.iiarjournals.org/content/11/3/115.abstract
AB 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.