title: RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer.
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.
authors.affiliation: a Simmons Cancer Center; UT Southwestern ; Dallas , TX USA.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.forename: A Kathleen
authors.initials: AK
authors.lastname: McClendon
authors.forename: Jorge
authors.initials: J
authors.lastname: Franco
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: EMT; MYC; RB tumor suppressor; Triple negative breast cancer; basal-like breast cancer; biomarkers; cell cycle; p53; targeted therapy