ABSTRACT
Transcriptional repressor zinc finger and BTB domain containing 1 (ZBTB1) is required for DNA repair. Because DNA repair defects often underlie genome instability and tumorigenesis, we determined to study the role of ZBTB1 in cancer. In this study, we found that ZBTB1 is down-regulated in breast cancer and this down-regulation is associated with poor outcome of breast cancer patients. ZBTB1 suppresses breast cancer cell proliferation and tumor growth. The majority of breast cancers are estrogen receptor (ER) positive and selective estrogen receptor modulators such as tamoxifen have been widely used in the treatment of these patients. Unfortunately, many patients develop resistance to endocrine therapy. Tamoxifen-resistant cancer cells often exhibit higher HER2 expression and an increase of glycolysis. Our data revealed that ZBTB1 plays a critical role in tamoxifen resistance in vitro and in vivo To see if ZBTB1 regulates HER2 expression, we tested the recruitments of ZBTB1 on HER2 regulatory sequences. We observed that over-expressed ZBTB1 occupies the estrogen receptor α (ERα)-binding site of the HER2 intron in tamoxifen-resistant cells, suppressing tamoxifen-induced transcription. In an effort to identify potential microRNAs (miRNAs) regulating ZBTB1, we found that miR-23b-3p directly targets ZBTB1. MiR-23b-3p regulates HER2 expression and tamoxifen resistance via targeting ZBTB1. Finally, we found that miR-23b-3p/ZBTB1 regulates aerobic glycolysis in tamoxifen-resistant cells. Together, our data demonstrate that ZBTB1 is a tumor suppressor in breast cancer cells and that targeting the miR-23b-3p/ZBTB1 may serve as a potential therapeutic approach for the treatment of tamoxifen resistant breast cancer.
Subject(s)
Breast Neoplasms/metabolism , Drug Resistance, Neoplasm/drug effects , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Glycolysis/drug effects , Receptor, ErbB-2/biosynthesis , Repressor Proteins/metabolism , Tamoxifen/pharmacology , Tumor Suppressor Proteins/metabolism , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Drug Resistance, Neoplasm/genetics , Female , Glycolysis/genetics , Humans , MCF-7 Cells , Mice , Mice, Nude , Receptor, ErbB-2/genetics , Repressor Proteins/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
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 ERß 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.
