title: Estrogen receptor α regulates non-canonical autophagy that provides stress resistance to neuroblastoma and breast cancer cells and involves BAG3 function.
abstract: 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, ERα 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 ERα or ERβ as well as the breast cancer-derived MCF-7 cell line endogenously expressing ERα but being ERβ negative. We could show that ERα-expressing cells have a higher autophagic activity than cells expressing ERβ and cells lacking ER expression. Additionally, for autophagy-related gene expression we describe an ERα-specific 'autophagy-footprint' that is fundamentally different to tumor cells expressing ERβ or lacking ER expression. This newly described ERα-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 ERα-positive breast cancer cells that do not respond to anti-hormone therapy and classical autophagy inhibitors.
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Felzen
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Hiebel
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Koziollek-Drechsler
authors.affiliation: Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Reißig
authors.affiliation: Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Wolfrum
authors.affiliation: Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Frankfurt, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kögel
authors.affiliation: Department of Medicine, Hematology/Oncology and University Cancer Center Frankfurt, Goethe University Hospital, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Brandts
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Behl
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Morawe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D047629:Estrogen Receptor beta / Q000096:biosynthesis / Q000235:genetics; D015914:Estrogen Replacement Therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D057285:Precision Medicine; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta