Circular RNAs: novel regulators of resistance to systemic treatments in breast cancer.

Systematic treatments including chemotherapy, endocrine therapy, and HER2-targeted therapy are important therapeutic approaches to breast cancer. However, drug resistance is a major barrier to achieving a cure in breast cancer (BC) patients. Hence, it is urgent to gain insight into the drug-resistance mechanisms in order to improve the prognosis of BC patients. Genetic alternations, epigenetic alternations, and other non-genetic mechanisms such as BC stem-like cells, metabolic reprogramming, and tumor microenvironment contribute to drug resistance of BC. With the development of single-cell sequencing of circulating tumor cell and next-generation sequencing of matched pre- and post- progression tumor biopsies or ctDNA from BC patients with drug resistance, new mechanisms of resistance are being discovered. An increasing number of microRNAs and long non-coding RNAs have been found to be associated with the drug resistance of BC. However, there are few reports on the role of circular RNAs (circRNAs) as master regulators of drug resistance. Therefore, there is still much to say in the field of drug resistance-related circRNAs. In this review, we mainly focus on literature evidence for the detailed mechanisms associated with systematic treatments' resistance of BC and how circRNAs intensify or weaken drug resistance. Exogenous expression of tumor suppressive circRNAs or knockdown of oncogenic circRNAs has been verified to reverse drug resistance of BC cells, which highlights that circRNAs may function as potential biomarkers and/or therapeutic targets of BC. Treatment targeting abnormally expressed circRNAs alone or combined with other systemic treatments may be a promising approach to conquering drug resistance.