1. ¹Cancer Research Institute, University of California San Francisco, San Francisco, CA, USA
2. ²University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
3. ³Department of Hematology and Medical Oncology, Hospital Clinico, Valencia, Spain
4. ⁴Division of Oncology, Center for Applied Medical Research CIMA, University of Navarra, Pamplona, Spain
5. ⁵Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
6. ⁶Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA

Correspondence: Dr DG Albertson, Cancer Research Institute, University of California San Francisco, San Francisco Comprehensive Cancer Center, 2340 Sutter Street, Box 0808, San Francisco, CA 94143-0808, USA. E-mail: albertson@cc.ucsf.edu

⁷Current address: Department of Hematology/Oncology, University of California San Francisco, San Francisco, CA 94143, USA

⁸Current address: Epitomics, 863 Mitten Road, Suite 103, Burlingame, CA 94010, USA

⁹Current address: Department of Early Clinical Development Statistics, Genentech Inc., South San Francisco, CA, USA

Received 8 December 2008; Revised 24 January 2009; Accepted 12 February 2009; Published online 30 March 2009.

Abstract

Co-amplification at chromosomes 8p11–8p12 and 11q12–11q14 occurs often in breast tumors, suggesting possible cooperation between genes in these regions in oncogenesis. We used high-resolution array comparative genomic hybridization (array CGH) to map the minimal amplified regions. The 8p and 11q amplicons are complex and consist of at least four amplicon cores at each site. Candidate oncogenes mapping to these regions were identified by combining copy number and RNA and protein expression analyses. These studies also suggested that CCND1 at 11q13 induced expression of ZNF703 mapping at 8p12, which was subsequently shown to be mediated by the Rb/E2F pathway. Nine candidate oncogenes from 8p12 and four from 11q13 were further evaluated for oncogenic function. None of the genes individually promoted colony formation in soft agar or collaborated with each other functionally. On the other hand, FGFR1 and DDHD2 at 8p12 cooperated functionally with MYC, whereas CCND1 and ZNF703 cooperated with a dominant negative form of TP53. These observations highlight the complexity and functional consequences of the genomic rearrangements that occur in these breast cancer amplicons, including transcriptional cross-talk between genes in the 8p and 11q amplicons, as well as their cooperation with major pathways of tumorigenesis.