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

Abstract

AbstractBreast 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.

Autoren

V Felzen
C Hiebel
I Koziollek-Drechsler
S Reißig
U Wolfrum
D Kögel
C Brandts
C Behl
T Morawe

DOI

10.1038/cddis.2015.181

eISSN

2041-4889

Ausgabe der Veröffentlichung

7

Zeitschrift

Cell Death & Disease

Sprache

en

Online publication date

2015

Paginierung

e1812 - e1812

Status

Published online

Herausgeber

Springer Science and Business Media LLC

Herausgeber URL

http://dx.doi.org/10.1038/cddis.2015.181

Datum der Datenerfassung

2023

Titel

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

Ausgabe der Zeitschrift

6

Data source: Crossref

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.

Addresses

Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Autoren

V Felzen
C Hiebel
I Koziollek-Drechsler
S Reißig
U Wolfrum
D Kögel
C Brandts
C Behl
T Morawe

DOI

10.1038/cddis.2015.181

eISSN

2041-4889

Externe Identifier

PubMed Identifier: 26158518
PubMed Central ID: PMC4650728

Open access

true

ISSN

2041-4889

Zeitschrift

Cell death & disease

Schlüsselwörter

Humans
Neuroblastoma
Breast Neoplasms
Adaptor Proteins, Signal Transducing
Estrogen Receptor alpha
Estrogen Receptor beta
Estrogen Replacement Therapy
Signal Transduction
Gene Expression Regulation, Neoplastic
Autophagy
Female
Apoptosis Regulatory Proteins
MCF-7 Cells
Precision Medicine

Sprache

eng

Medium

Electronic

Online publication date

2015

Open access status

Open Access

Paginierung

e1812

Datum der Veröffentlichung

2015

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2015

Titel

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

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

6

Files

https://www.nature.com/articles/cddis2015181.pdf https://europepmc.org/articles/PMC4650728?pdf=render

Data source: Europe PubMed Central

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.

Date of acceptance

2015

Autoren

V Felzen
C Hiebel
I Koziollek-Drechsler
S Reißig
U Wolfrum
D Kögel
C Brandts
C Behl
T Morawe

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/26158518

DOI

10.1038/cddis.2015.181

eISSN

2041-4889

Externe Identifier

PubMed Central ID: PMC4650728

Ausgabe der Veröffentlichung

7

Zeitschrift

Cell Death Dis

Schlüsselwörter

Adaptor Proteins, Signal Transducing
Apoptosis Regulatory Proteins
Autophagy
Breast Neoplasms
Estrogen Receptor alpha
Estrogen Receptor beta
Estrogen Replacement Therapy
Female
Gene Expression Regulation, Neoplastic
Humans
MCF-7 Cells
Neuroblastoma
Precision Medicine
Signal Transduction

Sprache

eng

Country

England

Paginierung

e1812

PII

cddis2015181

Datum der Veröffentlichung

2015

Status

Published online

Datum, an dem der Datensatz öffentlich gemacht wurde

2016

Titel

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

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

6

Data source: PubMed

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

Files

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