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

doi:10.1128/MCB.21.13.4265-4275.2001

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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 generatedby HER4 homodimers versus heterodimeric complexes with other EGFRfamily members. The ratio of homo- and heterodimeric complexesmay be influenced both by a cell's EGFR family member expressionprofile and by the ligand or even ligand isoform used. To definethe role of HER4 in mediating antiproliferative and differentiationresponses, human breast cancer cell lines were screened for responsesto heregulin. Only cells that expressed HER4 exhibited heregulin-dependentantiproliferative responses. In-depth studies of one line, SUM44,demonstrated that the antiproliferative and differentiation responsescorrelated with HER4 activation and were abolished by stable expressionof a kinase-inactive HER4. HB-EGF, a HER4-specific ligand in thisEGFR-negative cell line, also induced an antiproliferative response.Moreover, introduction and stable expression of HER4 in HER4-negativeSUM102 cells resulted in the acquisition of a heregulin-dependentantiproliferative response, associated with increases in markersof differentiation. The role of HER2 in these heregulin-dependentresponses was examined through elimination of cell surface HER2signaling by stable expression of a single-chain anti-HER2 antibodythat sequestered HER2 in the endoplasmic reticulum. In the celllines with either endogenously (SUM44) or exogenously (SUM102)expressed HER4, elimination of HER2 did not alter HER4-dependentdecreases in cell growth. These results suggest that HER4 is bothnecessary and sufficient to trigger an antiproliferative responsein human breast cancercells.

^* Corresponding author. Mailing address: Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, Universityof 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.

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