Abstract 5079: Role of syntaxin-1A, a synaptic-related protein, in HER2-enriched and luminal B breast cancer progression

Breast cancer (BC) is the most prevalent cancer in women. It can be classified into 4 subtypes according to their gene expression signature, each one characterized by its aggressiveness and treatment approach. Mortality has declined as a result of earlier diagnoses and the availability of adjuvant therapies. However, a significant number of patients do not respond to these therapies or develop resistance after an initial response. The therapies currently available fail at curing or preventing BC tumor progression and metastasis. Therefore, there is an urgent need to develop novel therapeutic tools to improve BCs patients´ survival rates. The interaction of cancer cells with the stroma has been well established and has led to exciting new therapies. However, the presence and relevance of nerve axons and their secreted neurotransmitters and neuropeptides in the tumor microenvironment has been acknowledged only very recently. We have identified 6 nervous system related genes differentially expressed in BC subtypes. Among them, Syntaxin-1A (STX1A) is up-regulated in luminal B and HER2-enriched tumors, and its expression significantly correlates with a shorter overall survival and metastasis free survival. Therefore, we hypothesized that STX1A regulates luminal B and HER2 enriched tumors progression and metastasis development. STX1A belongs to the soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins superfamily that regulate membrane fusion events, including exocytosis and neurotransmission, intracellular trafficking, and cell proliferation. To test its role in breast cancer we have characterized STX1A pathway in a panel of BC cells. Our results showed that STX1A is overexpressed in luminal B and HER2-enriched cell lines at protein and mRNA level, as we have seen in patient9s database. Moreover we have analyzed STX1A expression in cell lines that were derived either from lung or brain metastases respectively and we have discovered that the cells that have migrated to the brain or to the lung have increased STX1A expression in comparison to the parentals. Moreover, downregulation of STX1A using siRNA results in inhibition of epithelial to mesenchymal markers, such as Twist-1, indicating a possible role of STX1A in tumor cell migration and metastasis. Furthermore, downregulation of STX1A also represses FGFR2 activation, suggesting that STX1A might regulate tyrosine kinase receptors membrane trafficking. In conclusion we propose STXIA and SNARE proteins as potential biomarkers and targets for novel BC therapy. Citation Format: Aleix Noguera-Castells, Leire Recalde-Percaz, Nuria Moragas, Patricia Fernandez-Nogueira, Gemma Fuster, Anna Lopez-Plana, Patricia Jauregui, Pere Gascon, Paloma Bragado, Mario Mancino. Role of syntaxin-1A, a synaptic-related protein, in HER2-enriched and luminal B breast cancer progression [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 5079.