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Dual inhibition of Type I and Type III PI3 kinases increases tumor cell apoptosis in HER2+ breast cancers

Overview of attention for article published in Breast Cancer Research, December 2015
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  • Above-average Attention Score compared to outputs of the same age (56th percentile)
  • Average Attention Score compared to outputs of the same age and source

Mentioned by

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4 tweeters
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1 Facebook page

Citations

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6 Dimensions

Readers on

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12 Mendeley
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Title
Dual inhibition of Type I and Type III PI3 kinases increases tumor cell apoptosis in HER2+ breast cancers
Published in
Breast Cancer Research, December 2015
DOI 10.1186/s13058-015-0656-2
Pubmed ID
Authors

Christian D. Young, Carlos L. Arteaga, Rebecca S. Cook

Abstract

Human epidermal growth factor receptor-2 (HER2) gene amplification (HER2+) drives tumor cell growth and survival in ~25 % of breast cancers. HER2 signaling activates the type I phosphoinositide 3-kinase (PI3K), upon which these tumors rely. Consequently, inhibitors of HER2 and type I PI3K block growth and increase apoptosis in HER2+ breast cancers, especially when used in combination. However, the impact of type III PI3K inhibition, particularly in combination with HER2 blockade or type I PI3K inhibition, remains less clear. We utilized small molecule kinase inhibitors, locked nucleic acid antisense oligonucleotides (LNA-ASOs), and siRNA to assess proliferation, autophagy, apoptosis, and protein expression in cell culture models of HER2+ breast cancers. Treatment of HER2+ breast cancer cells with HER2 inhibitors or type I PI3K kinase inhibitors, alone or in combination, blocked type I PI3K signaling, reduced tumor cell growth, and induced autophagy. Knockdown of the type I PI3K, p110α, using an LNA-ASO termed EZN4150 inhibited PI3K-mediated Akt phosphorylation. However, in contrast to catalytic inhibitors of type I PI3Ks, EZN4150 did not induce autophagy, and blocked autophagy in response to inhibitors of HER2 or type I PI3Ks in a dominant fashion. Sequence analysis of EZN4150 revealed significant homology to the gene encoding the type III PI3K, Vps34, a key component for autophagy induction. EZN4150 simultaneously reduced expression of both p110α and Vps34. Combined inhibition of PI3K signaling and autophagy using individual siRNAs against p110α and Vps34 or using pharmacological type I and type III PI3K inhibitors recapitulated what was seen with EZN4150, and robustly enhanced tumor cell killing. These studies highlight the important role of Vps34-mediated autophagy in limiting the anti-tumor response to inhibitors of HER2 or type I PI3K in HER2+ breast cancers. The type III PI3K Vps34 represents a potential therapeutic target to block treatment-induced autophagy and enhance tumor cell killing.

Twitter Demographics

The data shown below were collected from the profiles of 4 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 12 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 12 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 5 42%
Student > Bachelor 3 25%
Researcher 2 17%
Professor > Associate Professor 1 8%
Student > Postgraduate 1 8%
Other 0 0%
Readers by discipline Count As %
Medicine and Dentistry 4 33%
Biochemistry, Genetics and Molecular Biology 4 33%
Agricultural and Biological Sciences 2 17%
Immunology and Microbiology 1 8%
Pharmacology, Toxicology and Pharmaceutical Science 1 8%
Other 0 0%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. 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 09 December 2015.
All research outputs
#7,576,139
of 13,457,546 outputs
Outputs from Breast Cancer Research
#940
of 1,511 outputs
Outputs of similar age
#149,161
of 358,063 outputs
Outputs of similar age from Breast Cancer Research
#87
of 138 outputs
Altmetric has tracked 13,457,546 research outputs across all sources so far. This one is in the 42nd percentile – i.e., 42% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,511 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 10.0. This one is in the 35th percentile – i.e., 35% 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 358,063 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 56% of its contemporaries.
We're also able to compare this research output to 138 others from the same source and published within six weeks on either side of this one. This one is in the 36th percentile – i.e., 36% of its contemporaries scored the same or lower than it.