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Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells.

Publication ,  Journal Article
Sartor, CI; Zhou, H; Kozlowska, E; Guttridge, K; Kawata, E; Caskey, L; Harrelson, J; Hynes, N; Ethier, S; Calvo, B; Earp, HS
Published in: Mol Cell Biol
July 2001

The function of the epidermal growth factor receptor (EGFR) family member HER4 remains unclear because its activating ligand, heregulin, results in either proliferation or differentiation. This variable response may stem from the range of signals generated by HER4 homodimers versus heterodimeric complexes with other EGFR family members. The ratio of homo- and heterodimeric complexes may be influenced both by a cell's EGFR family member expression profile and by the ligand or even ligand isoform used. To define the role of HER4 in mediating antiproliferative and differentiation responses, human breast cancer cell lines were screened for responses to heregulin. Only cells that expressed HER4 exhibited heregulin-dependent antiproliferative responses. In-depth studies of one line, SUM44, demonstrated that the antiproliferative and differentiation responses correlated with HER4 activation and were abolished by stable expression of a kinase-inactive HER4. HB-EGF, a HER4-specific ligand in this EGFR-negative cell line, also induced an antiproliferative response. Moreover, introduction and stable expression of HER4 in HER4-negative SUM102 cells resulted in the acquisition of a heregulin-dependent antiproliferative response, associated with increases in markers of differentiation. The role of HER2 in these heregulin-dependent responses was examined through elimination of cell surface HER2 signaling by stable expression of a single-chain anti-HER2 antibody that sequestered HER2 in the endoplasmic reticulum. In the cell lines with either endogenously (SUM44) or exogenously (SUM102) expressed HER4, elimination of HER2 did not alter HER4-dependent decreases in cell growth. These results suggest that HER4 is both necessary and sufficient to trigger an antiproliferative response in human breast cancer cells.

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Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

July 2001

Volume

21

Issue

13

Start / End Page

4265 / 4275

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Signal Transduction
  • Receptor, erbB-2
  • Receptor, ErbB-4
  • Receptor, ErbB-2
  • RNA, Messenger
  • Phosphotyrosine
  • Phosphorylation
  • Neuregulin-1
  • Ligands
 

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Sartor, C. I., Zhou, H., Kozlowska, E., Guttridge, K., Kawata, E., Caskey, L., … Earp, H. S. (2001). Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol, 21(13), 4265–4275. https://doi.org/10.1128/MCB.21.13.4265-4275.2001
Sartor, C. I., H. Zhou, E. Kozlowska, K. Guttridge, E. Kawata, L. Caskey, J. Harrelson, et al. “Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells.Mol Cell Biol 21, no. 13 (July 2001): 4265–75. https://doi.org/10.1128/MCB.21.13.4265-4275.2001.
Sartor CI, Zhou H, Kozlowska E, Guttridge K, Kawata E, Caskey L, et al. Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol. 2001 Jul;21(13):4265–75.
Sartor, C. I., et al. “Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells.Mol Cell Biol, vol. 21, no. 13, July 2001, pp. 4265–75. Pubmed, doi:10.1128/MCB.21.13.4265-4275.2001.
Sartor CI, Zhou H, Kozlowska E, Guttridge K, Kawata E, Caskey L, Harrelson J, Hynes N, Ethier S, Calvo B, Earp HS. Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol. 2001 Jul;21(13):4265–4275.

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

July 2001

Volume

21

Issue

13

Start / End Page

4265 / 4275

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Signal Transduction
  • Receptor, erbB-2
  • Receptor, ErbB-4
  • Receptor, ErbB-2
  • RNA, Messenger
  • Phosphotyrosine
  • Phosphorylation
  • Neuregulin-1
  • Ligands