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.
Highlights
Estrogen receptor (ER) a is the key mediator of estrogen functions in the breast and plays prominent roles in breast cancer [1,2,3]
We found that zinc finger and BTB domain containing 1 (ZBTB1) is down-regulated in breast cancer and the low expression of ZBTB1 indicates poor outcome in breast cancer treatments
Because ZBTB1 is down-regulated in breast cancer, we decided to carry out a series of experiments to examine the effect of ZBTB1 on the growth of breast cancer cells
Summary
Estrogen receptor (ER) a is the key mediator of estrogen functions in the breast and plays prominent roles in breast cancer [1,2,3]. HER2 overexpression is not the universal mechanism for all tamoxifen-resistant tumors, it is an important strategy to repress HER2 expression for overcoming tamoxifen resistance in some breast cancer patients. Paired box gene 2 has been shown to play a critical role in HER2 expression in tamoxifen-resistant cells and paired box gene 2 predicts clinical outcome of tamoxifen therapy in breast cancer patients [12, 27]. ZBTB1 sensitizes breast cancer cells to tamoxifen co-activators instead of co-repressors onto HER2 intron [27]. These findings suggest a new mechanism for HER2 regulation in ERa positive breast cancer [22, 27, 28]
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