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 ERa-positive breast cancer cell lines and tumor samples and is functionally important in promoting ERa-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 ERa-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 ERa-positive breast cancer cell and tumor growth, re-sensitizing tamoxifen-resistant ERa-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 ERa-positive breast cancer in the clinic.

Automated summary

This study found that circPVT1, a circular RNA derived from the lncRNA PVT1, is highly expressed in ERa-positive breast cancer cell lines and tumors and plays an important role in breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a ceRNA to sequester miR-181a-2-3p, promoting the expression of ESR1 and downstream ERa-target genes, and facilitates breast cancer cell growth. Additionally, circPVT1 interacts with MAVS protein, disrupting the RIGI-MAVS complex formation, inhibiting type I interferon signaling pathway and anti-tumor immunity. ASO targeting circPVT1 inhibits ERa-positive breast cancer cell and tumor growth, sensitizing tamoxifen-resistant ERa-positive breast cancer cells to tamoxifen treatment. Therefore, circPVT1 may serve as a diagnostic biomarker and therapeutic target for ERa-positive breast cancer in the clinic.