Jacob P S Johnson1, Prashant Kumar2, Miroslav Koulnis3, Milan Patel4, Karl Simin1. 1. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, U.S.A. 2. Institute of Molecular and Cell Biology, ASTAR, Singapore. 3. National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, U.S.A. 4. Wright Center for Graduate Medical Education, Scranton, PA, U.S.A.
Abstract
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. Copyright
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. Copyright
Authors: Andrew R Chin; Miranda Y Fong; George Somlo; Jun Wu; Piotr Swiderski; Xiwei Wu; Shizhen Emily Wang Journal: Cell Res Date: 2016-01-22 Impact factor: 25.617
Authors: S Yadavalli; S Jayaram; S S Manda; A K Madugundu; D S Nayakanti; T Z Tan; R Bhat; A Rangarajan; A Chatterjee; H Gowda; J P Thiery; P Kumar Journal: Sci Rep Date: 2017-03-06 Impact factor: 4.379