Cyclin D1 Splice Variants: Polymorphism, Risk, and Isoform-Specific Regulation in Prostate Cancer

Abstract

Purpose: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged. Experimental Design: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies.Results: Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated expression patterns, and hormone status did not alter splicing. Whereas G/ A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism. Conclusions: These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism. (Clin Cancer Res 2009;15(17):5338-49)

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

“…Consistent with the greater transforming potential of the constitutively nuclear D1a mutant, D1b transforms NIH-3T3 cells with much greater efficiency than does D1a (Solomon et al 2003). D1b has been shown to associate with the androgen receptor (AR), but, unlike D1a, D1b fails to inhibit AR transcriptional activity, a phenomenon of particular relevance to PCa, which shows frequent upregulation of cyclin D1b (Burd et al 2006;Comstock et al 2009). …”

“…A common polymorphism that occurs near the 59 splice site of exon 4 influences the extent of cyclin D1b produced. The G870A polymorphism, with a reported allele frequency of 42% in one European population, has been associated with production of D1b (Betticher et al 1995;Comstock et al 2009). The polymorphism occurs at the very last nucleotide of exon 4 and may affect the recognition of exon 4 by the splicing machinery.…”

Cyclin D1 rare variants in UK multiple adenoma and early-onset colorectal cancer patients

“…In addition, it is well-known that the common variant rs9344 A allele modifies a splicing donor site and predisposes for an alternatively spliced transcript of the cyclin D1 protein (cyclin D1b). 28 In transcript b, no splicing occurs at the exon 4-intron 4 boundary, and exon 5 is missing. 1 Most variants found in 3¢UTRs of the patients are reported to be within conserved blocks, as are the majority of the variants in the promoter regions and the exons.…”

“…However, examination of 2Â2 tables reveals that LD between the CCND1-10/13/20 haplotype and rs9344 is nevertheless highly significant ( Table 6). Given that it has been demonstrated that this polymorphism is not independently predictive of cancer and that additional events may be necessary to induce cyclin D1b production, 28 we examined whether the presence of rare variants along the CCND1 gene is in any way associated with genotype at this position. We found that patients who carry at least one rare variant are more likely to also carry the rs9344 G allele than cases who do not harbor rare variants.…”

The Role of SF2 in Prostate Cancer Progression

“…Unfortunately, little is known concerning the mechanisms, pathways, and/or components of splicing in PCa. Overall Scope: Previously it been demonstrated that cyclin D1, a key modulator of androgen/AR-dependent transcription and proliferation, is alternatively spliced in PCa (5). Published data have suggested that SF2 and cyclin D1 isoforms have oncogenic functions (6,7) suggesting a potential link between splicing and proliferation.…”