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Phosphatase and Tensin Homologue Deleted on Chromosome 10 Deficiency Accelerates Tumor Induction in a Mouse Model of ErbB-2 Mammary Tumorigenesis

¹ Molecular Oncology Group, McGill University Health Center; ² McGill Center for Bioinformatics, McGill University, Montreal, Quebec, Canada; and ³ Center for Comparative Medicine and Department of Pathology and Laboratory Medicine, School of Medicine, University of California Davis, Davis, California

Requests for reprints: William J. Muller, Molecular Oncology Group, McGill University Health Center, Montreal, Quebec, Canada H3A 1A1. Phone: 514-934-1934, ext. 36383; Fax: 514-843-1478; E-mail: william.muller{at}mcgill.ca.

Key Words: PTEN • ErbB-2 • mammary tumors • transgenic mouse models • basal-like subtype

Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and amplification or elevated expression of ErbB-2 are both involved in human breast cancer. To directly test the importance of these genetic events in mammary tumorigenesis, we have assessed whether mammary-specific disruption of PTEN could cooperate with activation of ErbB-2. Transgenic mice expressing ErbB-2 under the transcriptional control of its endogenous promoter (ErbB-2^KI) were interbred with mice carrying conditional PTEN alleles and an MMTV/Cre transgene. Loss of one or both PTEN alleles resulted in a dramatic acceleration of mammary tumor onset and an increased occurrence of lung metastases in the ErbB-2^KI strain. Tumor progression in PTEN-deficient/ErbB-2^KI strains was associated with elevated ErbB-2 protein levels, which were not due to ErbB-2 amplification or to a dramatic increase in ErbB-2 transcripts. Moreover, the PTEN-deficient/ErbB-2^KI–derived mouse mammary tumors display striking morphologic heterogeneity in comparison with the homogeneous pathology of the ErbB-2^KI parental strain. Therefore, inactivation of PTEN would not only have a dramatic effect on ErbB-2–induced mammary tumorigenesis but would also lead to the formation of mammary tumors that, in part, display pathologic and molecular features associated with the basal-like subtype of primary human breast cancer. [Cancer Res 2008;68(7):2122–31]

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