A WIDELY EXPRESSED TRANSCRIPTION FACTOR WITH MULTIPLE DNA-SEQUENCE SPECIFICITY, CTCF, IS LOCALIZED AT CHROMOSOME SEGMENT 16Q22.1 WITHIN ONEOF THE SMALLEST REGIONS OF OVERLAP FOR COMMON DELETIONS IN BREAST ANDPROSTATE CANCERS

The cellular protooncogene MYC encodes a nuclear transcription factor that is involved in regulating important cellular functions, including cell cycle progression, differentiation, and apoptosis. Dysregulated MYC expression appears critical to the development of various types of malignancies, and thus factors involved in regulating MYC expression may also play a key role in the pathogenesis of certain cancers. We ha ve cloned one such MYC regulatory factor, termed CTCF, which is a high ly evolutionarily conserved-11-zinc finger transcriptional factor poss essing multiple DNA sequence specificity. CTCF binds to a number of im portant regulatory regions within the 5' noncoding sequence of the hum an MYC oncogene, and it can regulate its transcription in several expe rimental systems. CTCF mRNA is expressed in cells of multiple differen t lineages. Enforced ectopic expression of CTCF inhibits cell growth i n culture. Southern blot analyses and fluorescence in situ hybridizati on (FISH) with normal human metaphase chromosomes showed that the huma n CTCF is a single-copy gene situated at chromosome locus 16q22. Cytog enetic studies have pointed out that chromosome abnormalities (deletio ns) at this locus frequently occur in many different human malignancie s, suggesting the presence of one or more tumor suppressor genes in th e region. To narrow down their localization, several loss of heterozyg osity (LOH) studies of chromosome arm 16q in sporadic breast and prost ate cancers have been carried out to define the most recurrent and sma llest region(s) of overlap (SRO) for commonly deleted chromosome arm 1 6q material. For CTCF to be considered as a candidate tumor suppressor gene associated with tumorigenesis, it should localize within one of the SROs at 16q. Fine-mapping of CTCF has enabled us to assign the CTC F gene to about a 2 centiMorgan (cM) interval of 16q22.1 between the s omatic cell hybrid breakpoints CY130(D) and CY4, which is between mark ers D16S186 (16AC16-101) and D16S496 (AFM214zg5). This relatively smal l region, containing the CTCF gene, overlaps the most Frequently obser ved SROs for common chromosomal deletions found in sporadic breast and prostate tumors. In one of four analyzed paired DNA samples from prim ary breast cancer patients, we have detected a tumor-specific rearrang ement of CTCF exons encoding the I I-zinc-finger domain. Therefore, ta ken together with other CTCF properties, localization of CTCF to a nar row cancer-associated chromosome region suggests that CTCF is a novel candidate tumor suppressor gene at 16q22.1. (C) 1998 Wiley-Liss, Inc.