Abstract P3-04-27: Delineating novel molecular pathways driving endocrine resistance in breast cancer

Abstract

Abstract Background Estrogen receptor (ER) is a main driver of tumor progression in ER+ metastatic breast cancer (MBC). The use of endocrine therapy can effectively control the disease in a large proportion of patients. However, the majority of MBC eventually become resistant and progress. To elucidate the mechanisms of acquired resistance to endocrine treatment is key in order to better select therapeutic partners and delay disease progression. Methods A panel of ER+ breast cancer cell lines initially sensitive to the selective estrogen receptor degrader (SERD) fulvestrant was exposed to increasing concentrations of this drug over several months to induce resistance. Cell proliferation was determined with the xCELLigence system. Protein expression was measured by phospho-kinase array and western blotting. RNA expression was evaluated by gene expression microarray analysis (Illumina) and validated by RT-qPCR. Cell cycle distribution was analyzed by flow cytometry. Results Using an unbiased approach to identify pathways that drive endocrine resistance, both the parental and the resistant cell models were studied. As expected, fulvestrant treatment resulted in G1-cell cycle arrest in the parental cell lines. In stark contrast, resistant cells bypassed fulvestrant-induced proliferation block despite a lower expression of genes driving mitotic progression compared to untreated parental cells. This gene expression pattern was coupled with a reduction of ER protein level in the resistant cells, which was in line with a significant decrease in the expression of ER-target genes. Our phospho-screen analysis showed a genotype specific down-modulation of p53 and up-regulation of several signaling components of mitogenic pathways in resistant cells compared to parental cells. Conclusions Our results suggest that acquired endocrine resistance is driven by multiple cell-specific mechanisms rather than a common molecular underpinning. Strikingly, there is one unique feature in our models, which is a cellular switch towards an ER-independent gene expression program. Ongoing in vitro and in vivo studies, aimed at further characterizing these cellular models, will provide valuable insights into the heterogeneity underlying the response to endocrine treatment observed in MBC patients. Citation Format: Bosch A, Staaf J, Akrap N, Kaminska KK, Borgquist S, Borg Å, Honeth G. Delineating novel molecular pathways driving endocrine resistance in breast cancer [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 P3-04-27.