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The FOXP1 Winged Helix Transcription Factor Is a Novel Candidate Tumor Suppressor Gene on Chromosome 3p¹

University of Oxford, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom [A. H. B., C. F., K. G., M. J., D. Y. M., J. L. C.]; Wharton Head and Neck Centre, Princess Margaret Hospital, Toronto, Ontario, M5G 2 M9 Canada [N. B.]; Laboratory of Pathology, Hospital Clinic, IDIBAPS, University of Barcelona, 08036-Barcelona, Spain [E. C., P. L. F.]; Life Science R&D, Amersham Pharmacia Biotech, Amersham Laboratories, Amersham, Bucks HP7 9NA, United Kingdom [J. E. P.]; Pathology Department, Haemek Medical Center, 18101, Afula, Israel [P. T.]; and Department of Pathology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom [K. W.]

The JC12 monoclonal antibody recognizes a previously unknown nuclear protein that showed a restricted distribution in normal tonsil and was also overexpressed in a subset of diffuse large B-cell lymphomas. Using this reagent, we expression cloned cDNAs encoding its antigenic target and identified this protein as a novel putative transcription factor, FOXP1. The FOXP1 protein sequence contains predicted domains characteristic of transcription factors, including a winged helix DNA-binding motif, a second potential DNA-binding motif, a C₂H₂ zinc finger, nuclear localization signals, coiled-coil regions, PEST sequences, and potential transactivation domains. The FOXP1 gene has been mapped to chromosome 3p14.1, a region that commonly shows loss of heterozygosity in a wide range of tumors and which is reported to contain a tumor suppressor gene(s). Using tissue arrays and immunohistochemistry, we demonstrate that both the FOXP1 mRNA and protein are widely expressed in normal tissues. The levels of FOXP1 mRNA were compared in paired normal and tumor tissues (from the same patient) using a tissue array containing cDNAs extracted from 68 samples taken from kidney, breast, prostate, uterus, ovary, cervix, colon, lung, stomach, rectum, small intestine, and from nine cancer cell lines. Differences in FOXP1 mRNA expression between normal and tumor samples were observed in 51% of cases. Most striking was the comparative loss of expression in 73% of colon tumors and comparative overexpression of FOXP1 mRNA in 75% of stomach tumors. Analysis of the FOXP1 mRNA expression in normal tissues (not taken from cancer patients) indicated that loss of FOXP1 expression may occur in some histologically normal tissues adjacent to tumors. Immunohistochemical analysis of FOXP1 protein expression was performed on 128 solid tumors, including 16 renal, 9 breast, 12 lung, 20 colon, 21 stomach, 10 head and neck, 35 prostate, and 5 pancreatic cases. Complete loss of expression, increased expression, and cytoplasmic mislocalization of the predominantly nuclear FOXP1 protein were frequently observed in neoplastic cells. Our study identifies FOXP1 as a new candidate tumor suppressor gene localized to the chromosome 3p14.1 region.

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