Breast Cancer: Circular RNAs Mediating Efficacy in Preclinical In Vivo Models

Abstract

In order to identify new targets and treatment modalities for breast cancer, we searched the literature for circular RNAs (circRNAs) with efficacy in preclinical breast cancer-related in vivo models. From our search, we identified 26 up-regulated and six down-regulated circRNAs which mediate efficacy in breast cancer-related preclinical in vivo models. We discuss reconstitution and inhibition of the identified circRNAs, as well as druggability and validation of the targets identified in the context of chemoresistance, inhibition of proliferation and metastasis. Pathways driven by suppressors of cytokines and high-mobility group proteins, nuclear factor κB and Hippo signaling emerged as important drivers of tumor growth and metastasis. The role of trefoil factor-1 with respect to metastasis of estrogen receptorpositive breast cancer also merits further investigation. In addition, mucin 19 has emerged as an unexplored target for treatment of breast cancer. Breast cancer (BC) is the most common malignancy in women worldwide and occurs as ductal and lobular carcinomas (1). According to the expression of hormone receptors (HR) such as estrogen-receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2), the following subtypes have been defined: Luminal A (HR+, HER2-), luminal B (HR+, HER2+), triple-negativeBC (HR-, HER2-) and HER2 enriched (2). The treatment of BC is dependent on the molecular subtype and includes surgery, radiotherapy, chemotherapy and targeted therapy with agents such as tamoxifen, aromatase inhibitors, trastuzumab, pertuzumab, Kadcyla (trastuzumab-emtansine), lapatinib, poly-(ADP)-ribose polymerase inhibitors for BC with BRCA DNA repair-associated mutations, cyclindependent kinase (CDK) 4/6 inhibitors, tumor spreadinhibiting bisphosphonates and recently also immunotherapy with pembrolizumab (Keytruda) (3-6). BC is curable in 70- 80% of patients with early-stage, non-metastatic disease (3). BC metastasizes to the bones, lungs, regional lymph nodes, liver and brain and metastases only poorly respond to therapies (7, 8). Another problem is the development of resistance to chemotherapy and targeted therapies (9, 10). In order to identify new targets and treatment modalities for BC, we searched the literature for circular RNAs (circRNAs) with efficacy in preclinical BC-related in vivo models. We excluded triple-negative BC because relevant circRNAs in this subtype will be summarized in a separate review.