Abstract 2898: ST8SIA1 is up-regulated in triple negative breast cancer and its expression is positively correlated with TP53 mutations and a cancer stem cell gene signature

Abstract

Abstract We discovered ganglioside GD2 as a breast cancer stem cell (BCSCs) marker in triple negative breast cancer (TNBC). GD2 biosynthesis is tightly regulated by the enzyme ST8SIA1 (GD3 synthase). However, expression of ST8SIA and its association with different breast cancer sub-types is not known. Here we hypothesize that ST8SIA1 is up-regulated in TNBC or “basal-type” breast tumors and associated with stemness in primary breast tumors. To investigate ST8SIA1 expression in primary tumors, we analyzed RNAseq data from the cancer genome atlas (TCGA) data base, which includes data from 1105 primary and metastatic breast tumors as well as adjacent normal tissues. We found that ST8SIA1 expression varied widely among different breast tumors. Interestingly, “basal-type” tumors expressed the highest levels of ST8SIA1 compared to all other types of breast cancers including luminal-A or luminal-B or HER2-enriched tumors (p < 0.01). In addition, TNBC (n = 115) expressed 4.6-fold higher ST8SIA1 levels compared to hormone receptors positive tumors including ER+ or PR+ or HER2+ tumors (n = 852, p<0.001). Survival analysis by log-rank test indicated that patients with ST8SIA1high tumors survive shorter (median survival 2.6 years) compared to patients with ST8SIA1low tumors (median survival 4.3 years). Next, we investigates the association between ST8SIA1expression and the most commonly mutated genes in breast cancer. We chose the top 20 most frequently mutated genes in TCGA dataset and examined their correlation with ST8SIA1 mRNA expression. We found that, among the top 20 mutations, TP53 had a very strong positive correlation with ST8SIA1 expression (p < 0.00001). In fact, the expression of ST8SIA1 was > 2-fold higher in TP53-mutated compared to wild type tumors. The other positively correlated mutation was a nuclear envelop protein called the spectrin repeat containing protein (nuclear envelope 1 or SYNE1; p < 0.05). Mutations in GATA3 were the most negatively correlated (p < 0.001) with ST8SIA1 expression. Interestingly, GATA3 plays a role in epithelial cell differentiation in the mammary gland, supporting the notion that ST8SIA1 is a stem cell-associated gene. In addition, correlation of ST8SIA1 mRNA expression with other genes revealed that FOXA1, the protein which is co-expressed with GATA3 and serves as negative predictor of “basal-type” of breast cancer, was down regulated in ST8SIA1high tumors. In conclusion, ST8SIA1 is associated with “basal-type” TNBC tumors and it has a strong positive correlation with TP53 mutations and negative correlation with GATA3 mutations. Knowing that TP53 mutations have a major role in tumorigenesis and drug resistance, these data suggest that ST8SIA1 could be a potential therapeutic target in patients with TP53-mutant TNBC. Citation Format: V. Lokesh Battula, Yuanqing Yan, Khoa Nguyen, Kim-Anh Do, Michael Andreeff. ST8SIA1 is up-regulated in triple negative breast cancer and its expression is positively correlated with TP53 mutations and a cancer stem cell gene signature [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 2898. doi:10.1158/1538-7445.AM2017-2898