Norcantharidin regulates ERα signaling and tamoxifen resistance via targeting miR-873/CDK3 in breast cancer cells

Abstract

MiR-873/CDK3 has been shown to play a critical role in ERα signaling and tamoxifen resistance. Thus, targeting this pathway may be a potential therapeutic approach for the treatment of ER positive breast cancer especially tamoxifen resistant subtype. Here we report that Norcantharidin (NCTD), currently used clinically as an ani-cancer drug in China, regulates miR-873/CDK3 axis in breast cancer cells. NCTD decreases the transcriptional activity of ERα but not ERβ through the modulation of miR-873/CDK3 axis. We also found that NCTD inhibits cell proliferation and tumor growth and miR-873/CDK3 axis mediates cell proliferation suppression of NCTD. More important, we found that NCTD sensitizes resistant cells to tamoxifen. NCTD inhibits tamoxifen induced the transcriptional activity as well ERα downstream gene expressions in tamoxifen resistant breast cancer cells. In addition, we found that NCTD restores tamoxifen induced recruitments of ERα co-repressors N-CoR and SMRT. Knockdown of miR-873 and overexpression of CDK3 diminish the effect of NCTD on tamoxifen resistance. Our data shows that NCTD regulates ERα signaling and tamoxifen resistance by targeting miR-873/CDK3 axis in breast cancer cells. This study may provide an alternative therapy strategy for tamoxifen resistant breast cancer.

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

“…MiR-4472 is involved in chemoresistance and cancer development [157]. The study of the molecular pathways has shown that the EMT mechanism can be induced by miR-4472 during cancer progression [158]. Overall, stimulation of the EMT mechanism is a positive factor in tumor metastasis and migration, while it is associated with the poor prognosis of cancer patients [159,160].…”

MicroRNAs as a clue to overcome breast cancer treatment resistance

“…Low mir-873 levels were found in TAM-resistant cells together with overexpression CDK3, which is a direct target of miR-873 and responsible for ERα phosphorylation. Induction of miR-873 restored TAM sensitivity by decreasing the ERα transcriptional activity and ERα recruitment on ERE sequences in a CDK3-dependent manner [161,162].…”

Epi-miRNAs: Regulators of the Histone Modification Machinery in Human Cancer

“…miR-873 controls CDK3 activity, and decreased levels of this miRNA have been described in breast cancer [ 177 ]. miR-873 shifts tamoxifen resistance by targeting CDK3 and inducing ER phosphorylation [ 219 ]. miR-4469 is another noncoding RNA that targets CDK3 elevation in primary breast tumors compared to metastatic ones [ 178 ].…”