Article

Twist contributes to hormone resistance in breast cancer by downregulating estrogen receptor-α

Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21250, USA.
Oncogene (Impact Factor: 8.56). 11/2011; 31(27):3223-34. DOI: 10.1038/onc.2011.483
Source: PubMed

ABSTRACT The role of estrogen receptor-α (ER) in breast cancer development, and as a primary clinical marker for breast cancer prognosis, has been well documented. In this study, we identified the oncogenic protein, TWIST1 (Twist), which is overexpressed in high-grade breast cancers, as a potential negative regulator of ER expression. Functional characterization of ER regulation by Twist was performed using Twist low (MCF-7, T-47D) and Twist high (Hs 578T, MDA-MB-231, MCF-7/Twist) expressing cell lines. All Twist high expressing cell lines exhibited low ER transcript and protein levels. By chromatin immunoprecipitation and promoter assays, we demonstrated that Twist could directly bind to E-boxes in the ER promoter and significantly downregulate ER promoter activity in vitro. Functionally, Twist overexpression caused estrogen-independent proliferation of breast cells, and promoted hormone resistance to the selective estrogen receptor modulator tamoxifen and selective estrogen receptor down-regulator fulvestrant. Importantly, this effect was reversible on downregulating Twist. In addition, orthotopic tumors generated in mice using MCF-7/Twist cells were resistant to tamoxifen. These tumors had high vascular volume and permeability surface area, as determined by magnetic resonance imaging (MRI). Mechanistically, Twist recruited DNA methyltransferase 3B (DNMT3B) to the ER promoter, leading to a significantly higher degree of ER promoter methylation compared with parental cells. Furthermore, we demonstrated by co-immunoprecipitation that Twist interacted with histone deacetylase 1 (HDAC1) at the ER promoter, causing histone deacetylation and chromatin condensation, further reducing ER transcript levels. Functional re-expression of ER was achieved using the demethylating agent, 5-azacytidine, and the HDAC inhibitor, valproic acid. Finally, an inverse relationship was observed between Twist and ER expression in human breast tumors. In summary, the regulation of ER by Twist could be an underlying mechanism for the loss of ER activity observed in breast tumors, and may contribute to the generation of hormone-resistant, ER-negative breast cancer.

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    • "[44, 45]. This is also in agreement with recent studies showing that overexpression of TWIST induces ALDH1 expression in cell lines [46, 47]. "
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    • "Regarding its relevance to Twist1, Jun Hong et al.30 reported that high levels of total Twist1, phosphorylated Twist1 and activated JNK are associated with PR-negative status in breast tumors. Recently, Vesuna 31 and Fu 32 also found that Twist1 contributes to hormone resistance in breast cancer by down-regulating estrogen receptor-α. "
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    • "The latter (fulvestrant is the best known) bind to ERa and induce its proteasomal degradation [3]. However, most of these ER-positive breast tumors become hormone resistant and patients relapse within 5 years [2], giving rise to a need for novel antiestrogens with new potential properties. The withanolides are C-28 steroidal lactones and lactols isolated from several genera of the Solanaceae family [4], that exhibit a variety of biological activities including potential anticancer activity on breast cancer cells [5e8]. "
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