Abstract 991: OVO-like genes are master regulators of the epithelial fate in breast cancer

Abstract

Abstract The OVO-like genes are evolutionary conserved C2H2 zinc finger transcription factors (TFs) with SNAG repressor domains involved in the maintenance of epithelial homeostasis. From the three Ovo-like family genes identified in mammals, Ovol-like1 (Ovol1) and Ovol-like2 (Ovol2) are the most studied members with multiple reports pinpointing relevant roles in development and disease. In cancer, one of the hallmarks of invasive carcinoma involves the loss of E-cadherin expression by the repression of SNAG transcription factors. Interestingly, contrary to the other SNAG domain family members the OVO-like genes regulate epithelial cell fate. We performed data analysis in breast cancer cell lines and patient data obtained from GEO, CCLE, TCGA and METABRIC to assess the potential of the OVO-like genes as relevant regulators of gene expression in breast carcinoma. In addition, we stablished breast cancer models with inducible expression or repression of the OVO-like genes. We also analyzed the cellular systems we generated using naïve high-throughput methods such as RNA-Seq. Likewise, we studied the effect of OVO-like genes on tumor progression and metastasis using inducible expression systems in both xenograft and syngeneic breast cancer models. We observed that Ovol1 and Ovol2 are constitutively expressed in human breast cancer cell lines, and they are upregulated due to chromosomal gains in breast cancer patients. We observed how the introduction of Ovol1 and Ovol2 into mesenchymal-like breast cancer cell lines modified their transcriptome in a way that promoted expression of epithelial marker genes (e.g., Amphiregulin) and downregulated mesenchymal markers (e.g., Vimentin). In addition, introducing Ovo-like genes in mesenchymal-like cells greatly affected their viability and function. Surprisingly, we observed a similar effect by downregulating the Ovo-like genes in epithelial-like cells. We propose a model where a common epigenetic machinery is shared between structurally related transcription factors with opposing effects, such as OVO-like proteins and other SNAG-containing transcription factors, such as Snail and Slug, such that the abundance of the transcription factors and their co-repressors defines the state of the system as either epithelial or mesenchymal. Citation Format: Diana Drago Garcia, Yosef Yarden. OVO-like genes are master regulators of the epithelial fate in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 991.