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Molecular and Cellular Biology, June 2009, p. 3319-3331, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01803-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Naturally Occurring HER2 Carboxy-Terminal Fragment Promotes Mammary Tumor Growth and Metastasis ^,

Kim Pedersen,¹ Pier-Davide Angelini,^1,2 Sirle Laos,¹ Alba Bach-Faig,¹ Matthew P. Cunningham,¹ Cristina Ferrer-Ramón,¹ Antonio Luque-García,¹ Jesús García-Castillo,¹ Josep Lluis Parra-Palau,¹ Maurizio Scaltriti,¹ Santiago Ramón y Cajal,¹ José Baselga,¹ and Joaquín Arribas^1,2,3*

Medical Oncology Research Program, Research Institute Foundation and Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Psg. Vall d'Hebron 119-129, 08035 Barcelona, Spain,¹ Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Campus de la UAB, 08193 Bellaterra, Spain,² Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain³

Received 25 November 2008/ Returned for modification 3 February 2009/ Accepted 3 April 2009

HER2 is a tyrosine kinase receptor causally involved in cancer. A subgroup of breast cancer patients with particularly poor clinical outcomes expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTFs). However, since the CTFs lack the extracellular domain that drives dimerization and subsequent activation of full-length HER2, they are in principle expected to be inactive. Here we show that at low expression levels one of these fragments, 611-CTF, activated multiple signaling pathways because of its unanticipated ability to constitutively homodimerize. A transcriptomic analysis revealed that 611-CTF specifically controlled the expression of genes that we found to be correlated with poor prognosis in breast cancer. Among the 611-CTF-regulated genes were several that have previously been linked to metastasis, including those for MET, EPHA2, matrix metalloproteinase 1, interleukin 11, angiopoietin-like 4, and different integrins. It is thought that transgenic mice overexpressing HER2 in the mammary glands develop tumors only after acquisition of activating mutations in the transgene. In contrast, we show that expression of 611-CTF led to development of aggressive and invasive mammary tumors without the need for mutations. These results demonstrate that 611-CTF is a potent oncogene capable of promoting mammary tumor progression and metastasis.

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* Corresponding author. Mailing address: Medical Oncology Research Program, Vall d'Hebron University Hospital, Psg. Vall d'Hebron 119-129, 08035 Barcelona, Spain. Phone: 34 93 274 6026. Fax: 34 93 489 3884. E-mail: jarribas{at}ir.vhebron.net

Published ahead of print on 13 April 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, June 2009, p. 3319-3331, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01803-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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