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

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 22; pp. 8068 - 8073
• Main Authors: BEDNAREK, Andrzej K, KECK-WAGGONER, Catherine L, DANIEL, Rachael L, LAFLIN, Kendra J, BERGSAGEL, P. Leif, KIGUCHI, Kaoru, BRENNER, Andrew J, ALDAZ, C. Marcelo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.11.2001
• Subjects: Alternative Splicing; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Division - genetics; chromosome 16; Chromosomes, Human, Pair 16 - genetics; DNA Methylation; Exons; FRA16D gene; Gene Deletion; Genes, Tumor Suppressor; Green Fluorescent Proteins; Gynecology. Andrology. Obstetrics; Humans; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Mammary gland diseases; Medical sciences; Microscopy, Confocal; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Promoter Regions, Genetic; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Transfection; Tumor Cells, Cultured; Tumors; WWOX gene; Human; Cell proliferation; Alternative splicing; Molecular form; Nucleotide sequence; Tumoral tissue; Tumorigenicity; Malignant tumor; Gene expression; In vitro; Mammary gland diseases; Messenger RNA; Established cell line; Deletion; Mammary gland; Intracellular; Mutation; Localization; Mechanism of action; Tumor cell; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445

We recently reported the cloning of WWOX, a gene that maps to the common fragile site FRA16D region in chromosome 16q23.3-24.1. It was observed that the genomic area spanned by WWOX is affected by chromosomal translocations and homozygous deletions. Furthermore, the high incidence of allelic loss in breast, ovarian, prostate, and other cancers affecting this region suggests that WWOX is a candidate tumor suppressor gene. Expression of WWOX is highly variable in breast cancer cell lines, with some cases showing low or undetectable levels of expression. In this report, we demonstrate that ectopic WWOX expression strongly inhibits anchorage-independent growth in soft agar of breast cancer cell lines MDA-MB-435 and T47D. Additionally, we observed that WWOX induces a dramatic inhibition of tumorigenicity of MDA-MB-435 breast cancer cells when tested in vivo. We also detected the common occurrence of aberrant WWOX transcripts with deletions of exons 5-8 or 6-8 in various carcinoma cell lines, multiple myeloma cell lines, and primary breast tumors. These aberrant mRNA forms were not detected in normal tissues. Interestingly, we further observed that proteins encoded by such aberrant transcripts display an abnormal nuclear localization in contrast to the wild-type WWOX protein that localizes to the Golgi system. Our data indicate that WWOX behaves as a potent suppressor of tumor growth and suggest that abnormalities affecting this gene at the genomic and transcriptional level may be of relevance in carcinogenesis.