A role for macroautophagy in protection against 4-hydroxytamoxifen–induced cell death and the development of antiestrogen resistance

Abstract

This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor -positive (ER + ) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the antiestrogen-treated ER + breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT -induced cell death, but not 4-OHT -induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT-resistant cells selected from ER + breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER + , 4-OHT -resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER + breast cancer.

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

“…Autophagy is also able to protect cells from apoptosis and induce drug-resistance. Blocking autophagy restored anti-estrogen sensitivity to an MCF-7-derived anti-estrogen resistant cell line (29). Autophagy has also been implicated in the development of trastuzumab resistance in human epidermal growth factor receptor 2-positive breast cancer (30).…”

Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development

“…19 Also, downregulation of BECN1 with sh-BECN1 inhibited autophagy in MCF-7 cells. 17,19,[40][41][42] Although it is debatable whether BAF inhibits the fusion of autophagosomes and lysosomes, BAF is still used as an inhibitor to study autophagic flux in many studies. 43 Recently, Shingu et al reported that imatinib, a drug of molecular targeted therapy, induced autophagy in human malignant glioma cells.…”

“…17,18 A series of studies reported that chemotherapy induced-autophagy promotes the survival of some kinds of cancer cell lines. [19][20][21][22][23] These results suggest that autophagy might be involved in the development of chemotherapy resistance.…”

The Prolyl Isomerase Pin1 Induces LC-3 Expression and Mediates Tamoxifen Resistance in Breast Cancer

“…Autophagy is a key mechanism of cell survival in ER-positive breast cancer cells, resulting in the development of tamoxifen resistance (21). Also, antiestrogen resistance could be reduced by targeting autophagosome function, which is regulated by LC-3, Beclin-1, Atg-5, and Atg-12 (21)(22)(23), suggested that high Pin1 expression in tamoxifen-resistant MCF7 cells may enhance autophagy through increased expression of autophagy-related proteins, such as LC-3, to produce tamoxifen resistance. As expected, LC-3 levels were higher in tamoxifen-resistant MCF7 cells, and Pin1 overexpression produces the same expression patterns as tamoxifen-resistant cells, suggesting that Pin1 regulates tamoxifen resistance via enhanced LC-3 expression (Fig.…”