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

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.

Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype

“…Indeed, while 10 uM tamoxifen was able to transiently alkalinize the lysosome after 3 h treatment, measured by a reduction in lysotracker staining, ospemifene was not effective at a similar concentration (Fig EV5C). Also, we confirm previous data showing that the effect of tamoxifen on lysosomal alkalinization is reversible (Fig EV5C) (Actis et al , 2021).…”

Zinc in Cognitive Impairment and Aging

“…MtnA also responds to genes and pathways of additional metabolic processes, autophagy, and apoptosis [ 229 ]. Overexpression of MT in cells can protect lysosomes from estrogen-induced damage and maintain viability while inhibiting autophagy [ 230 ]. Knockdown of metallothionein-3 inhibits late autophagy in irradiated glioma cells [ 231 ].…”

The role of hypoxia-inducible factor-1 alpha in multidrug-resistant breast cancer

“…In addition, a study utilizing RT-PCR to measure ATG5 levels in 60 breast cancer tissues found that trastuzumab-resistant patients had higher ATG5 levels than trastuzumab effective patients ( 92 ). Similarly, elevated autophagy markers in drug-resistant breast cancer cells have been reported for tamoxifen and fulvestran ( 93 , 94 ). In summary, it can be concluded that HIF-1α can lead to breast cancer resistance to endocrine drugs and cytotoxic drugs through upregulation of autophagy.…”