Abstract 1975: FAM83B: A novel regulator of cell plasticity in breast cancer

Abstract

Abstract Epithelial to mesenchymal transition (EMT) is an important process in both metastasis and cancer stem cell (CSC) enrichment. Recent studies suggest that instead of simply transitioning from one cell state to another, cancer cells exist along a continuum of epithelial and mesenchymal cell states. Identifying novel regulators of tumor cell plasticity will be critical to fully understand this continuum and to target metastasis and CSC phenotypes in the future. FAM83B is a novel oncogene identified by the Jackson Laboratory in a forward genetic screen for drivers of Human Mammary Epithelial Cell (HMEC) transformation. Previous work showed that FAM83B expression is elevated in triple negative breast cancers and that FAM83B also activates key cell signaling pathways (EGFR, MAPK, and PI3K) in breast cancers. Here, we implicate FAM83B as a novel regulator of epithelial-mesenchymal plasticity using a HMEC transformation model. Transformation of primary HMEC by expressing shp16, shp53, c-Myc, and RAS results in the generation of two distinct transformed cell populations. One population retains epithelial characteristics, while an emergent population spontaneously acquires a mesenchymal morphology and a CD24LOCD44HI (CSC) cell surface marker profile. Moreover, isolation of epithelial, CD24HICD44LO cells (non-CSC) and exposure to Oncostatin M (OSM), an EMT-inducing cytokine, can also generate cells with a mesenchymal/CSC phenotype. Interestingly, FAM83B expression was significantly elevated in the epithelial/non-CSC population compared to the mesenchymal/CSC population. Moreover, treatment of purified epithelial/non-CSC cells with OSM resulted in decreased FAM83B expression levels, indicating FAM83B expression is suppressed as the cells move through EMT. FAM83B expression also correlated with an epithelial phenotype in a panel of breast cancer cell lines. shRNA-mediated knock-down of FAM83B from epithelial/non-CSC resulted in increased spontaneous EMT, concomitant with elevated expression of the mesenchymal marker Vimentin and master EMT transcription factor Zeb1. Following treatment with OSM, sh83B cells maintain prolonged, elevated p-Stat3 and p-ERK signaling, known contributors to the mesenchymal/CSC phenotype. Conversely, OSM-induced EMT was blunted in epithelial/non-CSC expressing exogenous FAM83B. Thus, FAM83B expression is a determinant in maintaining an epithelial phenotype, while suppression of FAM83B is important during EMT. Future work will seek to define novel FAM83B-mediated signaling pathways important for regulating cellular plasticity. Citation Format: Courtney A. Bartel, Damian J. Junk, Mark W. Jackson. FAM83B: A novel regulator of cell plasticity in 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 1975. doi:10.1158/1538-7445.AM2017-1975