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 report that circPVT1, a circular RNA generated from the lncRNA PVT1, is highly expressed in ERα‐positive breast cancer cell lines and tumor samples and is functionally important in promoting ERα‐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 ERα‐target genes and breast cancer cell growth. Furthermore, circPVT1 directly interacts with MAVS protein to disrupt the RIGI–MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti‐tumor immunity. Anti‐sense oligonucleotide (ASO)‐targeting circPVT1 inhibits ERα‐positive breast cancer cell and tumor growth, re‐sensitizing tamoxifen‐resistant ERα‐positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffolding mechanisms to promote cancer. Thus, circPVT1 may serve as a diagnostic biomarker and therapeutic target for ERα‐positive breast cancer in the clinic. Synopsis Estrogen receptor (ER)α, encoded by ESR1 , promotes mammary malignancies and is targeted in cancer therapy; however, resistance arises frequently. This study reports a novel circRNA, termed circPVT1, with dual mechanisms to enhance ER‐positive breast tumorigenesis, suggesting therapeutic opportunities. CircPVT1 is highly expressed in ERα‐positive breast tumor patients. CircPVT1 sponges miR‐181a‐2‐3p to stabilize ESR1 mRNA, activating the expression of estrogen/ERα‐target genes. CircPVT1 interacts with MAVS protein to disrupt RIGI–MAVS complex formation, repressing the expression of type I IFN and interferon‐stimulated genes. ASO‐targeting circPVT1 suppresses ERα‐positive breast cancer cell and tumor growth. Graphical Abstract Circular RNA circPVT1 has dual function in aggravating ER + mammary gland malignancies.