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

Cell Death Dis. 2015 Jul 9;6(7):e1812. doi: 10.1038/cddis.2015.181.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis*
  • Adaptor Proteins, Signal Transducing / genetics
  • Apoptosis Regulatory Proteins / biosynthesis*
  • Apoptosis Regulatory Proteins / genetics
  • Autophagy / genetics
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Estrogen Receptor alpha / biosynthesis*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor beta / biosynthesis
  • Estrogen Receptor beta / genetics
  • Estrogen Replacement Therapy
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MCF-7 Cells
  • Neuroblastoma / drug therapy
  • Neuroblastoma / genetics*
  • Neuroblastoma / pathology
  • Precision Medicine
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BAG3 protein, human
  • Estrogen Receptor alpha
  • Estrogen Receptor beta