Abstract 4864: Role of AIB1 Δ -4 in malignant progression of breast cancer

Abstract The nuclear co activator AIB1 is amplified and/or overexpressed in up to 60 % of breast cancers. We have previously described a splice variant of AIB1 (Δ4) missing exon 4 that results in an N-terminally truncated protein. Full length AIB1 transcriptional function can be repressed by the tumor supressor ANCO1/ANKRD11. However, Δ4 is missing the ANCO1 binding domain and is not transcriptionally suppressed. More metastatic variants of isogenic breast or colon cancer cell lines have significantly increased levels of Δ4 relative to full length protein. Δ4 levels also increase in breast tissue samples as they transition in malignant progression. We conjectured that small increases in Δ4 protein in the cell could have potent effects on malignant progression. To determine the functional significance of Δ4 in malignant progression we developed DCIS (ductal carcinoma in situ) cell lines that only express this isoform and not the full length protein. We engineered these lines by using CRISPR technology targeted at the exon 3/4 splice junction. The resulting lines were significantly more invasive in ECIS endothelial invasion assays. In vivo, intracardiac zebrafish injections of the Δ4-DCIS lines showed higher extravasation from the tail vasculature compared to the parental line. Subcutaneous xenografts in athymic nude mice grew larger tumors, presented more invasive lesions and metastases. Also, Δ4-DCIS spheres growing in matrigel, showed disorganization and enhanced invasion into the matrix. In conclusion these data suggest a model where the increased splicing of AIB1 to the Δ4 variant alters transcription at specific target genes and contributes to the metastatic phenotype. Citation Format: Ghada M. Sharif, Virginie Ory, Anton Wellstein, Anna Riegel. Role of AIB1 Δ -4 in malignant progression of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4864. doi:10.1158/1538-7445.AM2017-4864