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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,  α  and  β , ER α  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 anti-hormone 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 α  or ER β  as well as the breast cancer-derived MCF-7 cell line endogenously expressing ER α  but being ER β  negative. We could show that ER α -expressing cells have a higher autophagic activity than cells expressing ER β  and cells lacking ER expression. Additionally, for autophagy-related gene expression we describe an ER α -specific ‘ autophagy-footprint ' that is fundamentally different to tumor cells expressing ER β  or lacking ER expression. This newly described ER α -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 α -positive breast cancer cells that do not respond to anti-hormone therapy and classical autophagy inhibitors.

cell death and disease

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