Abstract 376: Therapeutic role of ESR1-CCDC170 gene fusion in breast cancer endocrine resistance

Abstract

Abstract Background: Gene fusions resulting from genomic rearrangements are important drivers for cancer initiation and progression. Estrogen receptor-positive (ER+) breast cancer is the most common type of breast cancer, and luminal B confers a more aggressive phenotype and higher risk of early relapse and prone to resistance to endocrine therapy. Identify new druggable genetic driver will be critical to improve clinical outcome of aggressive luminal B tumors. Our lab has identified a recurrent rearrangement between the estrogen receptor gene ESR1 and its neighbor gene CCDC170, in 6-8% of luminal B tumors. The exon 2 of ESR1 fused with the exon 6, 7, 8 or 10 of CCDC170, which enables the expression of different-sized N-terminally truncated CCDC170 (ΔCCDC170) under ESR1 promoter. Ectopic expression of ΔCCDC170 led to malignant transformation phenotypes in ER+ breast cancer cells, such as increase the cell migration, invasion and anchor-independent cell growth, as well as enhance xenograft tumor growth in mice. Methods: The effect of ESR1-CCDC170 on endocrine resistance was examined by cologenic assay in vitro, and by xenograft mouse model in vivo. Bioinformatics approaches, Reverse Phase Protein Array (RPPA) analysis and Bimolecular Fluorescence Complementation assay were used to elucidate the potential molecular mechanism. Results: This study aimed to determine the role of ESR1-CCDC170 in breast cancer endocrine resistance and elucidate the potential mechanisms as well as the therapeutic effect thereof. Our results show that ectopic expression of fusion variants in ER+ T47D cell line sustains the cell proliferation ability under estrogen deprivation (ED), and decreases the sensitivity to 4-OH Tamoxifen treatment. While silencing of ESR1-CCDC170 in fusion positive HCC1428 cell line increases the sensitivity to 4-OHTamoxifen and Fulvestrant treatment. Results from T47D xenograft tumor models show that ESR1-CCDC170 fusion induces endocrine resistance in vivo. Further mechanism studies show that ESR1-CCDC170 possesses a potential ATP binding pocket, has the ability to form homodimers. Conclusion: These results demonstrate the important role of ESR1-CCDC170 fusions in breast cancer endocrine resistance, and suggest that ESR1-CCDC170 fusion could be a potential therapeutic target for the treatment of breast cancer. Citation Format: Li Li, Jamunarani Veeraraghavan, Yiheng Hu, Xian Wang, Ying Tan, Rachel Schiff, Xiaosong Wang. Therapeutic role of ESR1-CCDC170 gene fusion in breast cancer endocrine resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 376.