Journal article
RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer
Cell cycle (Georgetown, Tex.), v 14(1), pp 109-122
01 Jan 2015
PMID: 25602521
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Triple negative breast cancer (TNBC) is characterized by multiple genetic events occurring in concert to drive pathogenic features of the disease. Here we interrogated the coordinate impact of p53, RB, and MYC in a genetic model of TNBC, in parallel with the analysis of clinical specimens. Primary mouse mammary epithelial cells (mMEC) with defined genetic features were used to delineate the combined action of RB and/or p53 in the genesis of TNBC. In this context, the deletion of either RB or p53 alone and in combination increased the proliferation of mMEC; however, the cells did not have the capacity to invade in matrigel. Gene expression profiling revealed that loss of each tumor suppressor has effects related to proliferation, but RB loss in particular leads to alterations in gene expression associated with the epithelial-to-mesenchymal transition. The overexpression of MYC in combination with p53 loss or combined RB/p53 loss drove rapid cell growth. While the effects of MYC overexpression had a dominant impact on gene expression, loss of RB further enhanced the deregulation of a gene expression signature associated with invasion. Specific RB loss lead to enhanced invasion in boyden chambers assays and gave rise to tumors with minimal epithelial characteristics relative to RB-proficient models. Therapeutic screening revealed that RB-deficient cells were particularly resistant to agents targeting PI3K and MEK pathway. Consistent with the aggressive behavior of the preclinical models of MYC overexpression and RB loss, human TNBC tumors that express high levels of MYC and are devoid of RB have a particularly poor outcome. Together these results underscore the potency of tumor suppressor pathways in specifying the biology of breast cancer. Further, they demonstrate that MYC overexpression in concert with RB can promote a particularly aggressive form of TNBC.
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Details
- Title
- RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer
- Creators
- Erik S. Knudsen - Simmons Cancer Center; UT Southwestern; Dallas, TX USAA. Kathleen McClendon - Thomas Jefferson UniversityJorge Franco - The University of Texas Southwestern Medical CenterAdam Ertel - Thomas Jefferson UniversityPaolo Fortina - Thomas Jefferson UniversityAgnieszka K. Witkiewicz - South Australia Pathology
- Publication Details
- Cell cycle (Georgetown, Tex.), v 14(1), pp 109-122
- Publisher
- Taylor & Francis
- Number of pages
- 14
- Grant note
- R01CA129134 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000348737400014
- Scopus ID
- 2-s2.0-84929456514
- Other Identifier
- 991019176647804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology