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Molecular and Cellular Biology, July 2001, p. 4265-4275, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4265-4275.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

HER4 Mediates Ligand-Dependent Antiproliferative and Differentiation Responses in Human Breast Cancer Cells

Carolyn I. Sartor,1,2,* Hong Zhou,1,2 Ewa Kozlowska,2 Katherine Guttridge,2 Evelyn Kawata,2 Laura Caskey,2 Jennifer Harrelson,2 Nancy Hynes,3 Stephen Ethier,4 Benjamin Calvo,2,5 and H. Shelton Earp III2,6

Department of Radiation Oncology,1 Department of Surgery,5 Department of Internal Medicine and Pharmacology,6 and Lineberger Comprehensive Cancer Center,2 University of North Carolina, Chapel Hill, North Carolina; Friedrich Miescher Institut, Basel, Switzerland3; and Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan4

Received 2 October 2000/Returned for modification 11 December 2000/Accepted 28 March 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.

* Corresponding author. Mailing address: Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina, Campus Box 7512, Chapel Hill, NC 27599-7512. Phone: (919) 966-7700. Fax: (919) 966-7681.E-mail: sartor{at}radonc.unc.edu.

Molecular and Cellular Biology, July 2001, p. 4265-4275, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4265-4275.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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