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Molecular and Cellular Biology, September 2006, p. 6412-6424, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.01950-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Heregulin-Dependent Delay in Mitotic Progression Requires HER4 and BRCA1

Rebecca S. Muraoka-Cook,1,2 Laura S. Caskey,1 Melissa A. Sandahl,1 Debra M. Hunter,1 Carty Husted,1 Karen E. Strunk,1 Carolyn I. Sartor,1,3 William A. Rearick Jr.,1 Wesley McCall,1 Magdalene K. Sgagias,6 Kenneth H. Cowan,6 and H. Shelton Earp III1,4,5*

Lineberger Comprehensive Cancer Center,1 Departments of Genetics,2 Radiation Oncology,3 Medicine,4 Pharmacology,School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599,5 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 681986

Received 5 October 2005/ Returned for modification 30 November 2005/ Accepted 27 May 2006

HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G2/M progression of breast cancer cells. While investigating pathways of G2/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, 102 Mason Farm Road, Chapel Hill, NC 27599. Phone: (919) 966-6225. Fax: (919) 966-3015. E-mail: hse{at}med.unc.edu.

Molecular and Cellular Biology, September 2006, p. 6412-6424, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.01950-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Muraoka-Cook, R. S., Sandahl, M. A., Strunk, K. E., Miraglia, L. C., Husted, C., Hunter, D. M., Elenius, K., Chodosh, L. A., Earp, H. S. III (2009). ErbB4 Splice Variants Cyt1 and Cyt2 Differ by 16 Amino Acids and Exert Opposing Effects on the Mammary Epithelium In Vivo. Mol. Cell. Biol. 29: 4935-4948 [Abstract] [Full Text]  
  • Feng, S.-M., Muraoka-Cook, R. S., Hunter, D., Sandahl, M. A., Caskey, L. S., Miyazawa, K., Atfi, A., Earp, H. S. III (2009). The E3 Ubiquitin Ligase WWP1 Selectively Targets HER4 and Its Proteolytically Derived Signaling Isoforms for Degradation. Mol. Cell. Biol. 29: 892-906 [Abstract] [Full Text]  
  • Strunk, K. E., Husted, C., Miraglia, L. C., Sandahl, M., Rearick, W. A., Hunter, D. M., Earp, H. S. III, Muraoka-Cook, R. S. (2007). HER4 D-Box Sequences Regulate Mitotic Progression and Degradation of the Nuclear HER4 Cleavage Product s80HER4. Cancer Res. 67: 6582-6590 [Abstract] [Full Text]  


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