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

ABSTRACT: 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 ERα-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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220776 | GEO | 2023/02/06

REPOSITORIES: GEO

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Project description:MCM3 is one of several genes whose expression profile is markedly altered in tamoxifen-resistant breast cancer cell lines. We observed that increased MCM3 expression is associated with tamoxifen resistance. Knockdown of MCM3 resulted in increased susceptibility of tamoxifen-resistant breast cancer cell lines. Moreover, MCM3 expression is significantly associated with clinical outcome of endocrine treated receptor positive breast cancer. To understand the effect of MCM3 on the mechanism of endocrine resistance, we performed gene expression array on tamoxifen-resistant breast cancer cell lines. Here we show that MCM3 knockdown affects the expression of hundreds of genes. Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317) and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

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

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