Abstract
Tamoxifen is a drug commonly used in the treatment of breast cancer, especially for postmenopausal patients. However, its efficacy is limited by the development of drug resistance. Downregulation of estrogen receptor alpha (ERα) is an important mechanism of tamoxifen resistance. In recent years, with progress in research into the protective autophagy of drug-resistant cells and cell cycle regulators, major breakthroughs have been made in research on tamoxifen resistance. For a better understanding of the mechanism of tamoxifen resistance, protective autophagy, cell cycle regulators, and some transcription factors and enzymes regulating the expression of the estrogen receptor are summarized in this review. In addition, recent progress in reducing resistance to tamoxifen is reviewed. Finally, we discuss the possible research directions into tamoxifen resistance in the future to provide assistance for the clinical treatment of breast cancer.
Highlights
Breast cancer is the most common cancer in women (Bray et al, 2018), and endocrine therapy plays an important role in breast cancer treatment (Rugo et al, 2016)
Tamoxifen plays an important role in ER-positive breast cancer patients
Most methods to overcome breast cancer resistance are based on the mechanism of drug resistance, such as inhibition of the Receptor Tyrosine Kinases (RTKs) pathway, upregulation of ERα36, and blocking protective autophagy, cell cycle regulators and epithelial–mesenchymal transition (EMT)-like phenomenon
Summary
Breast cancer is the most common cancer in women (Bray et al, 2018), and endocrine therapy plays an important role in breast cancer treatment (Rugo et al, 2016). Tamoxifen is an antagonist of ERα66, and it is commonly used in the treatment of ER-positive breast cancers (Binkhorst et al, 2012); the efficacy is not satisfactory because of the development of tamoxifen resistance. RTKs (receptor tyrosine kinases) and the activation of the PI3K-PTEN/ AKT/mTOR pathway caused by the overexpression of RTKs are thought to be closely related to resistance to tamoxifen (Hosford and Miller, 2014; Yin et al, 2014). Tamoxifen can activate ERα36, which in turn activates MAPK, AKT, and other signaling pathways, leading to tamoxifen resistance (Tong et al, 2010). A large body of evidence has shown that protective autophagy, cell cycle regulators, and some transcription factors play a key role in tamoxifen resistance, such as KLF4 regulating drug resistance by regulating MAPK and the discovery of LEM4 (Gao et al, 2018; Jia et al, 2018). Scientists have proposed many methods to reduce drug resistance through these mechanisms and have made great progress
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