title: Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts.
abstract: Development of chromosomal instability (CIN) and consequent phenotypic heterogeneity represent common events during breast cancer progression. Breast carcinomas harboring extensive chromosomal aberrations display a more aggressive behavior characterized by chemoresistance and the propensity to give rise to distant metastases. The tumor suppressor p53 plays a key role in the maintenance of chromosomal stability and tissue homeostasis through activation of cell cycle checkpoints following DNA damage and control of centrosome duplication that ensures equal chromosome segregation during cell division. Furthermore, p53 suppresses CD44 expression and the acquisition of stem cell-like properties responsible for epithelial to mesenchymal transition (EMT) and metastasis. In this study we employed MCF-7 breast cancer cells with endogenous wild-type p53, an engineered MCF-7 variant (vMCF-7(DNP53)) overexpressing a dominant negative p53val135 mutant, and cells re-cultured from vMCF-7(DNP53) tumor xenografts. We carried out an integrative transcriptome and cytogenetic analysis to characterize the mechanistic linkage between loss of p53 function, EMT and consequent establishment of invasive gene signatures during breast cancer progression. We demonstrate that abrogation of p53 function drives the early transcriptome changes responsible for cell proliferation, EMT and survival, while further transcriptome changes that occur during in vivo tumor progression are mechanistically linked to the development of CIN leading to a more invasive and metastatic breast cancer phenotype. Here we identified distinct novel non-canonical transcriptome networks involved in cell proliferation, EMT, chemoresistance and invasion that arise following abrogation of p53 function in vitro and development of CIN in vivo. These studies also have important translational implications since some of the nodal genes identified here are 'druggable' making them appropriate molecular targets for the treatment of breast carcinomas displaying mutant p53, EMT, CIN and high metastatic potential.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic School of Medicine, Rochester, MN 55905, USA.
authors.forename: Antonino B
authors.initials: AB
authors.lastname: D'Assoro
authors.forename: Alexey
authors.initials: A
authors.lastname: Leontovich
authors.forename: Angela
authors.initials: A
authors.lastname: Amato
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Ayers-Ringler
authors.forename: Cosima
authors.initials: C
authors.lastname: Quatraro
authors.forename: Kari
authors.initials: K
authors.lastname: Hafner
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.forename: James
authors.initials: J
authors.lastname: Ingle
authors.forename: Franca
authors.initials: F
authors.lastname: Stivala
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Salisbury
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53