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Estrogen-mediated inactivation of FOXO3a by the G protein-coupled estrogen receptor GPER

Overview of attention for article published in BMC Cancer, October 2015
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2 tweeters

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19 Dimensions

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35 Mendeley
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Title
Estrogen-mediated inactivation of FOXO3a by the G protein-coupled estrogen receptor GPER
Published in
BMC Cancer, October 2015
DOI 10.1186/s12885-015-1699-6
Pubmed ID
Authors

Erin Zekas, Eric R. Prossnitz

Abstract

Estrogen (17β-estradiol) promotes the survival and proliferation of breast cancer cells and its receptors represent important therapeutic targets. The cellular actions of estrogen are mediated by the nuclear estrogen receptors ERα and ERβ as well as the 7-transmembrane spanning G protein-coupled estrogen receptor (GPER). We previously reported that estrogen activates the phosphoinositide 3-kinase (PI3Kinase) pathway via GPER, resulting in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production within the nucleus of breast cancer cells; however, the mechanisms and consequences of this activity remained unclear. MCF7 breast cancer cells were transfected with GFP-fused Forkhead box O3 (FOXO3) as a reporter to assess localization in response to estrogen stimulation. Inhibitors of PI3Kinases and EGFR were employed to determine the mechanisms of estrogen-mediated FOXO3a inactivation. Receptor knockdown with siRNA and the selective GPER agonist G-1 elucidated the estrogen receptor(s) responsible for estrogen-mediated FOXO3a inactivation. The effects of selective estrogen receptor modulators and downregulators (SERMs and SERDs) on FOXO3a in MCF7 cells were also determined. Cell survival (inhibition of apoptosis) was assessed by caspase activation. In the estrogen-responsive breast cancer cell line MCF7, FOXO3a inactivation occurs on a rapid time scale as a result of GPER, but not ERα, stimulation by estrogen, established by the GPER-selective agonist G-1 and knockdown of GPER and ERα. GPER-mediated inactivation of FOXO3a is effected by the p110α catalytic subunit of PI3Kinase as a result of transactivation of the EGFR. The SERMs tamoxifen and raloxifene, as well as the SERD ICI182,780, were active in mediating FOXO3a inactivation in a GPER-dependent manner. Additionally, estrogen-and G-1-mediated stimulation of MCF7 cells results in a decrease in caspase activation under proapoptotic conditions. Our results suggest that non-genomic signaling by GPER contributes, at least in part, to the survival of breast cancer cells, particularly in the presence of ER-targeted therapies involving SERMs and SERDs. Our results further suggest that GPER expression and FOXO3a localization could be utilized as prognostic markers in breast cancer therapy and that GPER antagonists could promote apoptosis in GPER-positive breast cancers, particularly in combination with chemotherapeutic and ER-targeted drugs, by antagonizing estrogen-mediated FOXO3a inactivation.

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 35 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
India 1 3%
Unknown 34 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 6 17%
Student > Master 5 14%
Student > Postgraduate 4 11%
Student > Doctoral Student 3 9%
Student > Bachelor 3 9%
Other 8 23%
Unknown 6 17%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 8 23%
Medicine and Dentistry 7 20%
Agricultural and Biological Sciences 7 20%
Pharmacology, Toxicology and Pharmaceutical Science 4 11%
Immunology and Microbiology 2 6%
Other 0 0%
Unknown 7 20%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 17 October 2015.
All research outputs
#4,416,173
of 6,278,272 outputs
Outputs from BMC Cancer
#1,676
of 3,069 outputs
Outputs of similar age
#123,819
of 195,299 outputs
Outputs of similar age from BMC Cancer
#107
of 225 outputs
Altmetric has tracked 6,278,272 research outputs across all sources so far. This one is in the 26th percentile – i.e., 26% of other outputs scored the same or lower than it.
So far Altmetric has tracked 3,069 research outputs from this source. They receive a mean Attention Score of 2.9. This one is in the 36th percentile – i.e., 36% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 195,299 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 32nd percentile – i.e., 32% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 225 others from the same source and published within six weeks on either side of this one. This one is in the 44th percentile – i.e., 44% of its contemporaries scored the same or lower than it.