These observations suggest a novel role of BMP-6/HO-1 cascade to relieve breast cancer metastasis by regulating the secretion of growth factors in tumor microenvironment.
Resistance to tamoxifen therapy represents a major barrier to the successful treatment of breast cancer, where a loss of or reduced ER-α level is considered a primary mechanism. Understanding how ER-α expression is regulated would provide insights into new intervention points to overcome tamoxifen resistance. In this study, we report that the expression of δEF1 is up-regulated by 17β-estradiol (E2) in MCF-7 cells in an ER-α-dependent manner, through either PI3K or NF-κB pathway. Ectopic expression of δEF1 in turn repressed ER-α transcription by binding to the E2-box on the ER-α promoter. At the tissue level of breast cancer, there is a strong and inverse correlation between the expression levels of δEF1 and ER-α. In MCF-7 cells, an elevated expression of δEF1 made the cells less sensitive to tamoxifen treatment, whereas overexpression of ER-α compromised the effects of δEF1 and restored the sensitivity. Also, depletion of δEF1 by RNA interference in MDA-MB-231 cells restored the expression of ER-α and tamoxifen sensitivity. In conclusion, we have identified an important role of δEF1 in the development of tamoxifen resistance in breast cancer. Inhibiting δEF1 to restore ER-α expression might represent a potential therapeutic strategy for overcoming endocrine resistance in breast cancer.
Background: Resistance to tamoxifen therapy is one of the major barriers to the successful treatment of breast cancer, and ER-α expression is currently the main biomarker of response to tamoxifen treatment. Elucidating the regulation of ER-α expression may provide new therapeutic targets for overcoming tamoxifen resistance. Materials and Methods: Quantitative RT-PCR, immunoblotting, and immunofluorescence were used to determine 17β-estradiol-induced expression of αEF1 and ER-α at the mRNA and protein levels in the presence or absence of ICI 182,780, PI-103, PKI, or BAY 11-7082. Luciferase assay was used to determine αEF1-driven transcriptional activities of the wild-type and mutant human ER-α promoters. Quantitative CHIP assay was used to detect the direct association of αEF1 with the wild-type human ER-α proximal promoter. Immunohistochemistry was used to determine the expression of αEF1 and ER-α protein in breast cancer specimens. Results: We found that 17β-estradiol up-regulated αEF1 expression in a dose- and time-dependent manner in MCF-7 breast cancer cells. Down-regulation of the ER-α significantly abolished this effect, showing that 17β-estradiol-induced expression of αEF1 is ER-dependent. Blockade of the PI3K or NF-κB pathway resulted in an interference on the up-regulation of αEF1 by 17β-estradiol. Interestingly, ectopic expression of αEF1 exhibited a repression on ER-α expression in MCF-7 cells. Luciferase and CHIP assays further confirmed that αEF1 transcriptionally inhibited the promoter activity of human ER-α by binding to its E2-box (CACCTG). Importantly, up-regulation of αEF1 expression rendered MCF-7 cells less sensitive to tamoxifen treatment, whereas adding ER-α comprised the effect of αEF1 on the cell sensitivity to tamoxifen. Through the study of breast cancer specimens, we found a strong inverse correlation between αEF1 and ER-α protein expression, further supporting the contribution of estrogen/αEF1/ER cascade to tamoxifen resistance in breast cancer. Conclusions: Our data indicates a key role of αEF1 in developing tamoxifen resistance in breast cancer, by altering ER-α expression. Given that re-expressing ER-α in ER-α-negative breast cancer can restore tamoxifen sensitivity, restoring ER-α expression by inhibiting αEF1 provides a potential new strategy for overcoming endocrine resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 284. doi:1538-7445.AM2012-284
Orally bioavailable selective estrogen receptor downregulators (SERDs) may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for breast cancer patients with disease progression following antiestrogen or aromatase inhibitor therapy. We report the design and synthesis of ZB716, a C-3 position boronic acid modified fulvestrant, which behaves as a steroidal SERD suitable for oral administration. ZB716 binds to ERa competitively at an IC50 of 4.1 nM as compared to 3.9 nM for fulvestrant, and it effectively downregulates ERa (IC50=12.7 nM) in both tamoxifen-sensitive (T47D) and tamoxifen-resistant (T47D/PKCa) breast cancer cells. It acts as an antiestrogen that exerts potent antiproliferative effects on tamoxifen-resistant breast cancer cells (MCF-7/TamR, T47D/PKCa, and T47D/Y537S). When orally administered to mice, rats, and Beagle dogs, ZB716 demonstrates superior oral bioavailability in all animal-based pharmacokinetic studies when compared to fulvestrant administered by subcutaneous injection. More importantly, orally administered ZB716 was found to potently inhibit xenograft tumor growth in mice. These pre-clinical data strongly suggest that ZB716 is a promising SERD drug that could offer significant improvement over existing SERD regimen of Faslodex. ZB716 is being prepared in an IND application for phase 1 clinical trial in ER+, HER2- advanced breast cancer patients. Citation Format: Wang G, Liu J, Zheng S, Miele L, Wiese T, Zhong Q, Guo S. An orally bioavailable selective estrogen receptor downregulator [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-11.
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