FAM83B mediates EGFR- and RAS-driven oncogenic transformation

J Clin Invest. 2012 Sep;122(9):3197-210. doi: 10.1172/JCI60517. Epub 2012 Aug 13.

Abstract

Aberrant regulation of growth signaling is a hallmark of cancer development that often occurs through the constitutive activation of growth factor receptors or their downstream effectors. Using validation-based insertional mutagenesis (VBIM), we identified family with sequence similarity 83, member B (FAM83B), based on its ability to substitute for RAS in the transformation of immortalized human mammary epithelial cells (HMECs). We found that FAM83B coprecipitated with a downstream effector of RAS, CRAF. Binding of FAM83B with CRAF disrupted CRAF/14-3-3 interactions and increased CRAF membrane localization, resulting in elevated MAPK and mammalian target of rapamycin (mTOR) signaling. Ablation of FAM83B inhibited the proliferation and malignant phenotype of tumor-derived cells or RAS-transformed HMECs, implicating FAM83B as a key intermediary in EGFR/RAS/MAPK signaling. Analysis of human tumor specimens revealed that FAM83B expression was significantly elevated in cancer and was associated with specific cancer subtypes, increased tumor grade, and decreased overall survival. Cumulatively, these results suggest that FAM83B is an oncogene and potentially represents a new target for therapeutic intervention.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / pharmacology
  • Base Sequence
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Drug Resistance, Neoplasm
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Erlotinib Hydrochloride
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Mammary Glands, Human / metabolism
  • Mammary Glands, Human / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Sequence Data
  • Neoplasm Proteins / metabolism*
  • Neoplasm Transplantation
  • Neoplasms / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-raf / metabolism
  • Quinazolines / pharmacology
  • RNA Interference
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Transcriptome
  • ras Proteins / metabolism*

Substances

  • Antineoplastic Agents
  • FAM83A protein, human
  • Neoplasm Proteins
  • Quinazolines
  • Erlotinib Hydrochloride
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • ErbB Receptors
  • Proto-Oncogene Proteins c-raf
  • ras Proteins