Autophagy Triggers Tamoxifen Resistance in Human Breast Cancer Cells by Preventing Drug-Induced Lysosomal Damage

SIMPLE SUMMARY: Endocrine therapy with tamoxifen or other endocrine drugs represents the standard treatment for estrogen receptor-positive breast cancer. In spite of effectiveness of this therapy, onset of drug resistance worsens the prognosis of about 30% of patients. Autophagy has recently been proposed as a key player of drug resistance, but the underlying mechanisms are not completely understood. In this research, the authors investigate how autophagy triggers drug resistance in breast cancer cells. The results evidence that tamoxifen affects lysosome integrity, which suggests that this effect may contribute to the anticancer activity of this drug. Activation of autophagy and overexpression of iron-binding proteins synergize in protecting the lysosomal compartment, restraining drug effectiveness in breast cancer cells. According to these results, tamoxifen-resistant cells show an increased autophagic flux and overexpress iron-binding proteins. These findings indicate that screening for the level of iron-binding proteins may help to identify patients at risk for developing drug resistance. ABSTRACT: Endocrine resistance is a major complication during treatment of estrogen receptor-positive breast cancer. Although autophagy has recently gained increasing consideration among the causative factors, the link between autophagy and endocrine resistance remains elusive. Here, we investigate the autophagy-based mechanisms of tamoxifen resistance in MCF7 cells. Tamoxifen (Tam) triggers autophagy and affects the lysosomal compartment of MCF7 cells, such that activated autophagy supports disposal of tamoxifen-damaged lysosomes by lysophagy. MCF7 cells resistant to 5 µM tamoxifen (MCF7-TamR) have a higher autophagic flux and an enhanced resistance to Tam-induced lysosomal alterations compared to parental cells, which suggests a correlation between the two events. MCF7-TamR cells overexpress messenger RNAs (mRNAs) for metallothionein 2A and ferritin heavy chain, and they are re-sensitized to Tam by inhibition of autophagy. Overexpressing these proteins in parental MCF7 cells protects lysosomes from Tam-induced damage and preserves viability, while inhibiting autophagy abrogates lysosome protection. Consistently, we also demonstrate that other breast cancer cells that overexpress selected mRNAs encoding iron-binding proteins are less sensitive to Tam-induced lysosomal damage when autophagy is activated. Collectively, our data demonstrate that autophagy triggers Tam resistance in breast cancer cells by favoring the lysosomal relocation of overexpressed factors that restrain tamoxifen-induced lysosomal damage.