WWOX, the FRA16D gene, behaves as a suppressor of tumor growth

We recently reported the cloning of WWOX, a gene that maps to the common fr agile site FRA16D region in chromosome 16q23.3-24.1. It was observed that t he genomic area spanned by WWOX is affected by chromosomal translocations a nd homozygous deletions. Furthermore, the high incidence of allelic loss in breast, ovarian, prostate, and other cancers affecting this region suggest s that WWOX is a candidate tumor suppressor gene. Expression of WWOX is hig hly variable in breast cancer cell lines, with some cases showing low or un detectable levels of expression. In this report, we demonstrate that ectopi c WWOX expression strongly inhibits anchorage-independent growth in soft ag ar of breast cancer cell lines MDA-MB-435 and T47D. Additionally, we observ ed that WWOX induces a dramatic inhibition of tumorigenicity of MDA-MB-435 breast cancer cells when tested in vivo. We also detected the common occurr ence of aberrant WWOX transcripts with deletions of exons 5-8 or 6-8 in var ious carcinoma cell lines, multiple myeloma cell lines, and primary breast tumors. These aberrant mRNA forms were not detected in normal tissues. Inte restingly, we further observed that proteins encoded by such aberrant trans cripts display an abnormal nuclear localization in contrast to the wild-typ e WWOX protein that localizes to the Golgi system. Our data indicate that W WOX behaves as a potent suppressor of tumor growth and suggest that abnorma lities affecting this gene at the genomic and transcriptional level may be of relevance in carcinogenesis.