MTA1 Promotes Autophagy and Resistance to Tamoxifen in ERα-Positive Breast Cancer Cell Line

Abstract

Autophagy, a cellular recycling process in which long-lived proteins and organelles are degraded, has recently been recognized to be associated with drug resistance in various cancers. Several studies have reported an increase in autophagy in tamoxifen-resistant breast cancer. Interestingly, we found metastasis-associated protein 1 (MTA1) to be overexpressed in tamoxifen-resistant MCF7 breast cancer cell line, raising a potential link between MTA1 overexpression and the autophagy-induced tamoxifen resistance. To investigate the involvement of MTA1 in tamoxifen resistance, we used RNA interference against MTA1 followed by 4-hydroxytamoxifen (4OHT) treatment in MCF7 cells. Our data showed that MTA1 knockdown sensitized cells to 4OHT. Moreover, we observed that the depletion of MTA1 resulted in the decrease in autophagic flux. The reduction was accompanied with the downregulation of LC3-II level, a well-known marker for autophagy. 4OHT is known to induce autophagy in cells, which is a stress response in order to maintain cellular homeostasis. However, 4OHT-induced autophagy is known to ironically lead to the resistance to the drug. Our data showed that MTA1 knockdown led to a decrease in 4OHT-induced autophagy. Through qRT-PCR experiment, we observed that MTA1 depletion correlated with the decrease in the upregulation of ATG9B, an autophagy-related gene involved in the recycling of LC3 protein, in the presence of 4OHT. Our observations may help to understand the role of MTA1 in the development of resistance to endocrine therapy for patients with ERα-positive breast cancer.