Progress in the Understanding of the Mechanism of Tamoxifen Resistance in Breast Cancer

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.

Keywords: autophagy; breast cancer; cell cycle regulators; resistance; tamoxifen.

FIGURE 1

The role of RTKs and ERα36 in the development of tamoxifen resistance. EGFR induces tamoxifen resistance by enhancing the glycolytic pathway. The increase in EGF signal transduction induces a decrease in P53 expression, which leads to the inhibition of cell proliferation. TAMs secrete CC-chemokine ligand 2 (CCL2), which activates the PI3K/AKT/mTOR pathway. NF-κB promotes the secretion of CCL2. ERα36 contributes to the upregulation of EGFR, which increases ERK phosphorylation. The decrease in IGF-1R expression leads to the inhibition of FoxO1 expression, which results in the development of tamoxifen resistance. IGF1R mediates the expression of PAK2 and leads to drug resistance.