Abstract P6-14-11: Exosome-mediated Circ-CRSP1 promotes tumor proliferation and metastasis through stabilizing ELAVL1 protein and suppresses anti-tumor immune response in regulating the progression of Triple-Negative Breast Cancer

Abstract

Abstract Background: Triple-negative breast cancer (TNBC) is one of the most malignant subtype of breast cancer. Lacking targetable molecular drivers, chemotherapy is almost the only effective systematic treatment for TNBC. Compared with other types of breast cancer, TNBC shows a higher long-term recurrence rate and worse prognostic outcome, and its main cause of death is tumor metastasis. Therefore, there is an urgent clinical need to explore underlying molecular mechanisms and find novel targets for therapeutic intervention, as well as biomarkers for early clinical diagnosis. Materials & Methods: To explore the signal pathways and target molecules related to tumor immunity by bioinformatics analysis of tissue samples [TNBC (n = 55), Her2 (n = 39), Luminal B (n = 30), Luminal A (n = 29), healthy (n = 11)]. Co-culture experiment was conducted to study the effect of TNBC-derived exosome-mediated molecules on the proliferation and migration of breast cancer. qRT-PCR assay was used to confirm the expression level of Circ-CRSP1 in tumor tissues, breast cancer cells, exosomes of breast cancer cells and serum exosomes of breast cancer patients. Overexpression and knockout experiments investigated the role of Circ-CRSP1 in promoting the proliferation and migration of TNBC cells. Protein molecular docking technique was used to predict the possible targeting binding protein ELAVL1, and molecular experiments and nude mice model were used to study the mechanism of Circ-CRSP1-ELAVL1 complex in tumor immunity. Results: TNBC-derived exosome-mediated molecular transmission promotes the proliferation and migration of breast cancer, and may promote distant metastasis of breast cancer by changing the tumor microenvironment (TME) before metastasis. Bioinformatics analysis of TNBC tumor samples confirmed that TNBC is strongly associated with tumor immune-related biological processes and signal pathways. Circ-CRSP1 is highly expressed in TNBC tumor tissues, TNBC cells, exosome derived from TNBC cells and serum exosomes of TNBC patients, and is related to the poor clinical prognosis of TNBC patients. Overexpression of Circ-CRSP1 enhanced the proliferation and migration ability of TNBC cells, and the expression levels of EMT and cell-cycle related genes altered. Circ-CRSP1 binds to protein ELAVL1 at the physical level. The target gene of Circ-CRSP1-ELAVL1 complex is involved in the immune response, and the overexpression of Circ-CRSP1 significantly down-regulates the expression level of immune-related genes. Conclusion: Exosome-mediated Circ-CRSP1 promotes the transport of ELAVL1 from nucleus to cytoplasm through targeted binding with ELAVL1, and then regulates cytoplasmic proliferation and metastasis and inhibits the stability and translation of anti-tumor immune-related gene mRNA, thus finally promotes the proliferation, invasion and metastasis of TNBC. This study can further understand the mechanism of circRNA in the growth and metastasis of TNBC from the theoretical level, further explore the feasibility of Circ-CRSP1 as a molecular target for gene therapy, and provide theoretical basis and pre-clinical data for Circ-CRSP1 in serum exosomes as a high risk screening index and prognostic marker for TNBC patients. Citation Format: Sujin Yang, Jinhai Tang. Exosome-mediated Circ-CRSP1 promotes tumor proliferation and metastasis through stabilizing ELAVL1 protein and suppresses anti-tumor immune response in regulating the progression of Triple-Negative Breast Cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-11.