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Convergent and divergent cellular responses by ErbB4 isoforms in mammary epithelial cells

Vikram B Wali1, Jonathan W Haskins2, Maureen Gilmore-Hebert2

  • 1Department of Pathology, Yale School of Medicine, New Haven, Connecticut vikram.wali@yale.edu.

Molecular Cancer Research : MCR
|May 16, 2014
PubMed
Abstract

Insights

ErbB4 (ERBB4/HER4) receptor isoforms have diverse roles in cell growth and cancer. This study identified new targets and pathways regulated by ErbB4, including the Hippo and mevalonate pathways, offering insights into mammary biology and cancer.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • ErbB4 (ERBB4/HER4) is a member of the EGFR family with variable associations with cancer, potentially due to its structural diversity.
  • Alternative mRNA splicing and proteolysis generate multiple ErbB4 isoforms, including membrane-anchored and soluble forms that regulate transcription.

Purpose of the Study:

  • To compare the signaling activities of full-length (FL) and soluble intracellular isoforms of ErbB4.
  • To identify novel ErbB4-regulated transcripts and molecular targets.

Main Methods:

  • Expression of four JM-a ErbB4 isoforms (FL, ICD CYT-1, ICD CYT-2) in isogenic MCF10A cells.
  • Analysis of biologic activities, including cell proliferation and invasion.
  • Transcriptional profiling and ChIP-seq experiments.
  • Validation in a luminal breast cancer cell line.

Main Results:

  • FL and ICD CYT-2 promoted cell proliferation and invasion; ICD CYT-1 suppressed cell growth.
  • Identified new ErbB4-regulated transcripts in proteases, YAP/Hippo pathway, mevalonate/cholesterol pathway, and cytokines.
  • Validated several transcripts in breast cancer cells.
  • ChIP-seq identified ADAP1, APOE, SPARC, STMN1, and MXD1 as novel ErbB4 molecular targets.

Conclusions:

  • ErbB4 isoforms exhibit diverse biological activities.
  • ErbB4 regulates the Hippo and mevalonate pathways, providing new insights into mammary epithelial processes and cancer.

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