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FBXO31 Is the Chromosome 16q24.3 Senescence Gene, a Candidate Breast Tumor Suppressor, and a Component of an SCF Complex

¹ Breast Cancer Genetics Group, Dame Roma Mitchell Cancer Research Laboratories, Department of Medicine, University of Adelaide and Hanson Institute, Institute of Medical and Veterinary Science Adelaide; ² Centre for Medical Genetics, Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, North Adelaide, South Australia, Australia; and ³ Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands

Requests for reprints: David F. Callen, Breast Cancer Genetics Group, Dame Roma Mitchell Cancer Research Laboratories, Institute of Medical and Veterinary Science, Hanson Institute Building, Frome Road, Adelaide, South Australia 5000, Australia. Phone: 618-8-222-3450; Fax: 618-8-222-3217; E-mail: david.callen{at}imvs.sa.gov.au.

A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumor cell lines. We have shown that FBXO31, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. FBXO31 has properties consistent with a tumor suppressor, because ectopic expression of FBXO31 in two breast cancer cell lines inhibited colony growth on plastic and inhibited cell proliferation in the MCF-7 cell line. In addition, compared with the relative expression in normal breast, levels of FBXO31 were down-regulated in breast tumor cell lines and primary tumors. FBXO31 was cell cycle regulated in the breast cell lines MCF-10A and SKBR3 with maximal expression from late G₂ to early G₁ phase. Ectopic expression of FBXO31 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G₁ phase of the cell cycle. FBXO31 contains an F-box domain and is associated with the proteins Skp1, Roc-1, and Cullin-1, suggesting that FBXO31 is a component of a SCF ubiquitination complex. We propose that FBXO31 functions as a tumor suppressor by generating SCF^FBXO31 complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation. (Cancer Res 2005; 65(24): 11304-313)

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