Abstract 854: The role of protocadherin, FAT2 in breast cancer

Abstract

Abstract Protocadherins are cell adhesion molecules that belong to the cadherin superfamily. They are novel cadherin like proteins predominantly associated with early development and morphogenesis, cell growth and patterning, cell-cell adhesion, cell motility (including cell invasion and migration). The Fat-protocadherins are derived from an ancestral Drosophila FAT like cadherin and are evolutionarily conserved. They have been primarily implicated in neuronal cell development and cancer. Several studies have implicated protocadherin dysfunction in cancer. Loss of protocadherin expression, chromosome deletion and epigenetic silencing have been implicated in kidney, prostate, colorectal and breast cancer. More recently they have been implicated in gastric tumors and gliomas. Based on these findings, protocadherins are thought to be tumor suppressors and in general seem to regulate cancer cell proliferation, migration and/or apoptosis. However, multiple exceptions have also been observed and individual protocadherin functions seem to be context-dependent, as some can be considered either tumor suppressors or proto-oncogenes according to the type of cancer being examined. The mechanistics of the roles of the protocadherins in neuronal development have been well dissected but most oncological studies have focused on their characterization as potential biomarkers while the molecular signaling pathways through which the protocadherins regulate growth, invasion and metastasis are still poorly understood. For example recent research has shown that FAT1 is repressed in oral cancer owing to homozygous deletion or epigenetic silencing and is preferentially downregulated in invasive breast cancer. On the other hand, FAT1 is upregulated in leukemia and prognosis of preB-ALL patients with FAT1 upregulation is poor. Therefore FAT1 is tumor suppressive or oncogenic in a context-dependent manner, while FAT4 is tumor suppressive. FAT2 is highly expressed in breast cancer and lung squamous cell carcinoma and the elevated expression of FAT2 is correlated with poor patient outcome.Our preliminary research analysis of the TCGA data from the Genomic Data Commons Portal shows that protocadherins FAT4 and FAT1 are among the top dysregulated genes in cancer. We have also determined that FAT2 has higher Copy Number Variation (CNV) gain events than loss events. Given that there is a well-known concordance between CNV and differential gene expression we believe that FAT2 has a paradoxical oncogenic role in breast cancer. Citation Format: Thomas Roache, Megan Sumera, Zalaila Laird, Amrita Datta. The role of protocadherin, FAT2 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 854.