Abstract P4-07-06: Yes-Associated Protein, a Proposed Tumour Suppressor, Is Inversely Correlated to Cyclin D1 in Breast Tumours and Associated with a Worse Prognosis

Abstract

Abstract Background: In breast cancer, cyclin D1 over-expression and CCND1 (11q13) gene amplification have been linked to a worse prognosis. Conversely, lower levels of cyclin D1 have also been correlated to an unfavourable outcome. In a microarray analysis of cyclin D1 silenced MDA-MB-231 cells we identified Yes-associated protein (YAP), located at 11q22, as one of the most down-regulated genes. As such, we aimed to determine the importance of YAP in relation to cyclin D1 in breast cancer biology. Material and methods: Validation of cyclin D1, YAP antibodies and protein levels were performed in MDA-MB-231, MDA-MB-468 and MCF-7 by western blot. YAP protein expression was examined by screening 144 breast tumours and gene expression assessed by meta-analysis of six previously published breast cancer datasets totalling 1107 tumours with clinical follow-up. Subsequent data analysis was performed in SPSS. Results: YAP protein levels were down-regulated in cyclin D1 silenced MDA-MB-231, MDA-MB-468 and MCF-7 cell lines as predicted by microarray analysis. Surprisingly, YAP and cyclin D1 were inversely correlated at both protein and gene level in primary tumours (p=0.004 and P<0.001). Amplification of the CCND1 gene was correlated to low YAP protein expression (P<0.001) in the screening tumour material. Low YAP mRNA was an independent prognostic factor of recurrence (HR= 1.30, 95% CI 1.009-1.678, p=0.043) in the gene expression dataset. This effect was particularly pronounced in the luminal A subtype of breast tumours. Discussion: The independent prognostic value of YAP strengthens the notion of this protein as a tumour suppressor in breast cancer. The regulation of YAP by cyclin D1 appears to occur on both the protein level as seen in cell lines, and on the chromosomal level in terms of 11q aberrations. The inverse correlation observed in the tumour materials between cyclin D1 and YAP may be partly explained by chromosomal rearrangements; the amplification of the CCND1 gene (11q13) is often accompanied by loss of the 11q22 region of the chromosome, harbouring the YAP locus. Further studies are ongoing to clarify the link between YAP and cyclin D1 in breast cancer biology. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-07-06.