CircPVT1 promotes ER-positive breast tumorigenesis and drug resistance by targeting ESR1 and MAVS

The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we reported that circPVT1, a circular RNA generated from lncRNA PVT1, is highly expressed in ERalpha-positive breast cancer cell lines and tumor samples, which is functionally important in promoting ERalpha-positive breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a competing endogenous RNA (ceRNA) to sponge miR-181a-2-3p, promoting the expression of ESR1 and downstream ERalpha-target genes and breast cancer cell growth. Meanwhile, circPVT1 directly interacts with MAVS to disrupt the RIGI-MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti-tumor immunity. The dual mechanisms both contribute to ERa-positive breast tumorigenesis. Anti-sense oligonucleotides (ASO) targeting circPVT1 was shown to inhibit ERalpha-positive breast cancer cell and tumor growth, and could re-sensitize tamoxifen-resistant ERalpha-positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffold mechanisms to promote cancer, and in particular, circPVT1 may serve as a diagnosis biomarker and therapeutic target for ERalpha-positive breast cancer in the clinic. Overall design: RNA-seq performed in this study was designed to understand the molecular mechanisms underlying circPVT1 in gene transcriptional regulation.