Abstract P6-07-26: ST8SIA1 is over-expressed in triple negative breast cancer and associated with p53 mutations

Abstract

Abstract Cancer stem cells constitute a small fraction of cells present in primary tumors, are highly tumorigenic, drug resistant and cause metastases. 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. Frist, we examined ST8SIA1 protein expression in breast cancer cell lines (n=12) and found up-regulation of ST8SIA1 in basal compared to luminal-type breast cancer cells. To investigate ST8SIA1's expression in primary tumors, we analyzed RNAseq data from the cancer genome atlas (TCGA) data base which has expression data from 1105 primary and metastatic breast tumors as well as adjacent normal tissues. We found that ST8SIA1 expression varies widely among different breast tumors and that 'basal' type tumors express highest levels of ST8SIA1 compared to all other types of breast cancers including luminal-A or luminal-B or HER2 enriched (p<0.01) tumors. In addition, triple negative breast cancer (TNBC, n=115) express 4.63fold 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 indicates that patients with ST8SIA1high tumors survive shorter (median survival 2.6 years) compared to patients with ST8SIA1low tumors (median survival 4.3 years). These data suggests that ST8SIA1 expression is associated with basal-like TNBC tumor types and high ST8SIA1 levels in tumors may shorten survival in TNBC patients. To investigate 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, p53 has a very strong positive correlation with ST8SIA1 expression (p<0.00001). The expression of ST8SIA1 is >2 fold higher in p53 mutated tumors compared to p53 wild type tumors. The other positively correlated mutation was a nuclear envelop protein called Spectrin Repeat Containing, Nuclear Envelope 1 (SYNE1; p<0.05). Mutations in GATA3 are 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, is down regulated in ST8SIA1high tumors. In conclusion, ST8SIA1 is associated with basal-type TNBC tumors and has a strong positive correlation with p53 mutations and negative correlation with GATA3 mutations. Knowing that TP53 mutations have a major role in tumorigenesis and drug resistance, these data suggest ST8SIA1 as a potential therapeutic target in TNBC patients with p53 mutations. Citation Format: Yan Y, Nguyen K, Do K-A, Ueno N, Andreeff M, Battula VL. ST8SIA1 is over-expressed in triple negative breast cancer and associated with p53 mutations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-26.