Estrogen receptor α regulates non-canonical autophagy that provides stress resistance to neuroblastoma and breast cancer cells and involves BAG3 function

Breast cancer is a heterogeneous disease and approximately 70% of newly diagnosed breast cancers are estrogen receptor (ER) positive. Out of the two ER types, alpha and beta, ER alpha is the only ER that is detectable by immunohistochemistry in breast cancer biopsies and is the predominant subtype expressed in breast tumor tissue. ER-positive tumors are currently treated with antihormone therapy to inhibit ER signaling. It is well known that breast cancer cells can develop endocrine resistance and resistance to anti-hormone therapy and this can be facilitated via the autophagy pathway, but so far the description of a detailed autophagy expression profile of ER-positive cancer cells is missing. In the present study, we characterized tumor cell lines ectopically expressing ER alpha or ER beta as well as the breast cancer-derived MCF-7 cell line endogenously expressing ER alpha but being ER beta negative. We could show that ER alpha-expressing cells have a higher autophagic activity than cells expressing ER beta and cells lacking ER expression. Additionally, for autophagy-related gene expression we describe an ER alpha-specific 'autophagy-footprint' that is fundamentally different to tumor cells expressing ER beta or lacking ER expression. This newly described ER alpha-mediated and estrogen response element (ERE)-independent non-canonical autophagy pathway, which involves the function of the co-chaperone Bcl2-associated athanogene 3 (BAG3), is independent of classical mammalian target of rapamycin (mTOR) and phosphatidylinositol 3 kinase (PI3K) signaling networks and provides stress resistance in our model systems. Altogether, our study uncovers a novel non-canonical autophagy pathway that might be an interesting target for personalized medicine and treatment of ER alpha-positive breast cancer cells that do not respond to anti-hormone therapy and classical autophagy inhibitors.