Abstract C150: High expression of SNAI2 is associated with the emergence of a highly motile fulvestrant-resistant phenotype and is an indicator of poor response to endocrine treatment in estrogen receptor-positive metastatic breast cancer

Abstract

Abstract Endocrine resistance is a major clinical problem and is associated with the acquisition of aggressive tumor spread and invasion. To investigate the association between endocrine resistance and tumor cell migration and invasion, we evaluated a panel of MCF7-based cell line models resistant to either tamoxifen, aromatase inhibitors or fulvestrant. Fulvestrant-resistant cell lines showed a significantly higher migration capacity than the parental fulvestrant-sensitive cell line. Gene expression profiling and data analysis using Ingenuity Pathway Analysis (IPA) of these fulvestrant-resistant/fulvestrant-sensitive cell lines identified potential genes involved in the promotion of invasive and aggressive characteristics in the fulvestrant-resistant phenotype, including SNAI2, a transcription repressor that promotes epithelial-mesenchymal transition and tumor metastasis. The higher gene and protein expression levels of SNAI2 in fulvestrant-resistant cells were confirmed by RT-qPCR, Western blotting and immunocytochemistry. Specific gene silencing using small interfering RNA (siRNA) against SNAI2 decreased the migratory capacity of fulvestrant-resistant cells in vitro. Clinical evaluation of SNAI2 expression in estrogen receptor-positive (ER+) metastatic tumor samples from patients treated with endocrine drugs in the advanced setting (N = 86) showed that tumors with higher expression of SNAI2 correlated significantly with shorter progression-free survival (p = 0.001). Our results suggest that upregulation of SNAI2 is associated with the emergence of a highly motile fulvestrant-resistant phenotype in vitro and may be a potential therapeutic target in combination with endocrine therapies in tumors expressing high levels of SNAI2. Citation Format: Carla L. Alves, Daniel Elias, Maria Lyng, Martin Bak, Anne E. Lykkesfeldt, Henrik J. Ditzel. High expression of SNAI2 is associated with the emergence of a highly motile fulvestrant-resistant phenotype and is an indicator of poor response to endocrine treatment in estrogen receptor-positive metastatic breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C150.