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

SUBMITTER: Felzen V

PROVIDER: S-EPMC4650728 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

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

Cell death & disease 20150709

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 resistan ...[more]

PMID: 26158518

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Project description:Hypoglycemia resulting from a negative energy balance (NEB) in periparturient cattle is the major reason for a reduced glycogen content in polymorphonuclear neutrophils (PMNs). The lack of glycogen induces PMNs dysfunction and is responsible for the high incidence of perinatal diseases. The perinatal period is accompanied by dramatic changes in sex hormones levels of which estrogen (17β-estradiol, E2) has been shown to be closely associated with PMNs function. However, the precise regulatory mechanism of E2 on glucose metabolism in cattle PMNs has not been elucidated. Cattle PMNs were cultured in RPMI 1640 with 2.5 (LG), 5.5 (NG) and 25 (HG) mM glucose and E2 at 20 (EL), 200 (EM) and 450 (EH) pg/mL. We found that E2 maintained PMNs viability in different glucose conditions, and promoted glycogen synthesis by inhibiting PFK1, G6PDH and GSK-3β activity in LG while enhancing PFK1 and G6PDH activity and inhibiting GSK-3β activity in HG. E2 increased the ATP content in LG but decreased it in HG. This indicated that the E2-induced increase/decrease of ATP content may be independent of glycolysis and the pentose phosphate pathway (PPP). Further analysis showed that E2 promoted the activity of hexokinase (HK) and GLUT1, GLUT4 and SGLT1 expression in LG, while inhibiting GLUT1, GLUT4 and SGLT1 expression in HG. Finally, we found that E2 increased LC3, ATG5 and Beclin1 expression, inhibited p62 expression, promoting AMPK-dependent autophagy in LG, but with the opposite effect in HG. Moreover, E2 increased the Bcl-2/Bax ratio and decreased the apoptosis rate of PMNs in LG but had the opposite effect in HG. These results showed that E2 could promote AMPK-dependent autophagy and inhibit apoptosis in response to glucose-deficient environments. This study elucidated the detailed mechanism by which E2 promotes glycogen storage through enhancing glucose uptake and retarding glycolysis and the PPP in LG. Autophagy is essential for providing ATP to maintain the survival and immune potential of PMNs. These results provided significant evidence for further understanding the effects of E2 on PMNs immune potential during the hypoglycemia accompanying perinatal NEB in cattle.

Dataset Information

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

Publications

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

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