Abstract 1929: ST8SIA1 is a novel therapeutic target in TNBC: Regulates FAK-PI3K-AKT-mTOR signaling to promote tumor growth and metastasis

We identified ganglioside GD2 as a breast cancer stem cell (BCSC) marker and that GD3 synthase (ST8SIA1) regulates GD2 expression and BCSC function. We have reported that GD2 is up-regulated in TNBC and inhibition of its expression by knockdown of ST8SIA1 inhibits tumor growth and metastasis. Here we hypothesize that ST8SIA1 is overexpressed in TNBC and regulates cell signaling downstream of GD2 to promote tumor growth and metastasis. RNA sequencing data analysis of TCGA dataset with over 1100 primary and metastatic breast tumors revealed that ST8SIA1 was overexpressed in around 10% of all breast cancer patients. Basal type tumors expressed the highest levels of ST8SIA1 compared to luminal-A, luminal-B, and HER2-enriched (p + , PR + , and HER2 + tumors (n=852, p high tumors had significantly lower overall and disease-free survival rates than did patients with ST8SIA1 low tumors (p=0.0148 and p=0.0109, respectively with 60months follow-up). To investigate the mechanism of the ST8ISA1-mediated regulation of tumor growth and metastasis, we performed a proteomic analysis of GD2 + and GD2 - SUM159 and MDA-MB-231 cells using antibody micro-arrays (Kinexus). After systematic data analysis and functional validation by western blotting, we found that FAK, PI3K, AKT, ERK, mTOR, and 4EBP1 were highly phosphorylated in GD2 + compared to in GD2 - SUM159 cells. As it is known that GD2 acts as a co-receptor on the cell surface and activates downstream signaling, we hypothesized that ST8SIA1 regulates PI3K-AKT-mTOR signaling in BCSCs through GD2. To test our hypothesis, we knocked out ST8SIA1 in SUM159 cells using CRISPR-Cas9 approach. As expected knockout (KO) of ST8SIA1 reduced percentage of GD2 + cells from 20±5% to Citation Format: Khoa Nguyen, Bin Yuan, Yuanqing Yan, Kim-Anh Do, Naoto T. Ueno, Michael Andreeff, Venkata Lokesh Battula. ST8SIA1 is a novel therapeutic target in TNBC: Regulates FAK-PI3K-AKT-mTOR signaling to promote tumor growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1929.