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Molecular and Cellular Biology, September 2009, p. 4935-4948, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01705-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

ErbB4 Splice Variants Cyt1 and Cyt2 Differ by 16 Amino Acids and Exert Opposing Effects on the Mammary Epithelium In Vivo{triangledown}

Rebecca S. Muraoka-Cook,1,2 Melissa A. Sandahl,1 Karen E. Strunk,1 Leah C. Miraglia,1 Carty Husted,1 Debra M. Hunter,1 Klaus Elenius,5 Lewis A. Chodosh,6 and H. Shelton Earp III1,3,4*

UNC Lineberger Comprehensive Cancer Center,1 Departments of Genetics,2 Medicine,3 Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599,4 MediCity Research Laboratory, Departments of Medical Biochemistry and Molecular Biology and Department of Oncology, University of Turku, Turku FIN-20520, Finland,5 Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-61606

Received 5 November 2008/ Returned for modification 11 December 2008/ Accepted 3 July 2009

Data concerning the prognostic value of ErbB4 in breast cancer and effects on cell growth have varied in published reports, perhaps due to the unknown signaling consequences of expression of the intracellular proteolytic ErbB4 s80HER4 fragment or due to differing signaling capabilities of alternatively spliced ErbB4 isoforms. One isoform (Cyt1) contains a 16-residue intracellular sequence that is absent from the other (Cyt2). We expressed s80Cyt1 and s80Cyt2 in HC11 mammary epithelial cells, finding diametrically opposed effects on the growth and organization of colonies in three-dimensional matrices. Whereas expression of s80Cyt1 decreased growth and increased the rate of three-dimensional lumen formation, that of s80Cyt2 increased proliferation without promoting lumen formation. These results were recapitulated in vivo, using doxycycline-inducible, mouse breast-transgenic expression of s80Cyt1 amd s80Cyt2. Expression of s80Cyt1 decreased growth of the mammary ductal epithelium, caused precocious STAT5a activation and lactogenic differentiation, and increased cell surface E-cadherin levels. Remarkably, ductal growth inhibition by s80Cyt1 occurred simultaneously with lobuloalveolar growth that was unimpeded by s80Cyt1, suggesting that the response to ErbB4 may be influenced by the epithelial subtype. In contrast, expression of s80Cyt2 caused epithelial hyperplasia, increased Wnt and nuclear β-catenin expression, and elevated expression of c-myc and cyclin D1 in the mammary epithelium. These results demonstrate that the Cyt1 and Cyt2 ErbB4 isoforms, differing by only 16 amino acids, exhibit markedly opposing effects on mammary epithelium growth and differentiation.

* Corresponding author. Mailing address: UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 102 Mason Farm Road, Chapel Hill, NC 27599. Phone: (919) 966-2335. Fax: (919) 966-3015. E-mail: hse{at}med.unc.edu

{triangledown} Published ahead of print on 13 July 2009.

Molecular and Cellular Biology, September 2009, p. 4935-4948, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01705-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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