FOXA1, GATA3 and PPARɣ Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines

Sci Rep. 2016 Dec 7:6:38531. doi: 10.1038/srep38531.

Abstract

Discrete bladder cancer molecular subtypes exhibit differential clinical aggressiveness and therapeutic response, which may have significant implications for identifying novel treatments for this common malignancy. However, research is hindered by the lack of suitable models to study each subtype. To address this limitation, we classified bladder cancer cell lines into molecular subtypes using publically available data in the Cancer Cell Line Encyclopedia (CCLE), guided by genomic characterization of bladder cancer by The Cancer Genome Atlas (TCGA). This identified a panel of bladder cancer cell lines which exhibit genetic alterations and gene expression patterns consistent with luminal and basal molecular subtypes of human disease. A subset of bladder cancer cell lines exhibit in vivo histomorphologic patterns consistent with luminal and basal subtypes, including papillary architecture and squamous differentiation. Using the molecular subtype assignments, and our own RNA-seq analysis, we found overexpression of GATA3 and FOXA1 cooperate with PPARɣ activation to drive transdifferentiation of a basal bladder cancer cells to a luminial phenotype. In summary, our analysis identified a set of human cell lines suitable for the study of molecular subtypes in bladder cancer, and furthermore indicates a cooperative regulatory network consisting of GATA3, FOXA1, and PPARɣ drive luminal cell fate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • GATA3 Transcription Factor / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genetic Association Studies
  • Hepatocyte Nuclear Factor 3-alpha / metabolism*
  • Humans
  • PPAR gamma / metabolism*
  • Rats
  • Regulatory Sequences, Nucleic Acid / genetics
  • Sequence Analysis, RNA
  • Urinary Bladder Neoplasms / classification*
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • Urothelium / pathology

Substances

  • Biomarkers, Tumor
  • FOXA1 protein, human
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • PPAR gamma