Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts

Antonino B. D'Assoro, Alexey Leontovich, Angela Amato, Jennifer R. Ayers-Ringler, Cosima Quatraro, Kari Hafner, Robert B. Jenkins, Massimo Libra, James Ingle, Franca Stivala, Evanthia Galanis, Jeffrey L. Salisbury

Research output: Contribution to journalArticle

11 Scopus citations

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-7DNP53) overexpressing a dominant negative p53val135 mutant, and cells re-cultured from vMCF-7DNP53 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.

Original languageEnglish (US)
Pages (from-to)1167-1176
Number of pages10
JournalInternational journal of oncology
Volume37
Issue number5
DOIs
StatePublished - Nov 1 2010

Keywords

  • Breast cancer
  • Centrosome amplification
  • Chromosomal instability
  • Epithelial mysenchymal transition
  • Invasive gene networks
  • Tumor cell heterogeneity
  • Tumor progression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts'. Together they form a unique fingerprint.

  • Cite this