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Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents

Overview of attention for article published in Breast Cancer Research, April 2015
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About this Attention Score

  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (80th percentile)
  • Good Attention Score compared to outputs of the same age and source (66th percentile)

Mentioned by

twitter
6 tweeters
facebook
1 Facebook page
wikipedia
1 Wikipedia page

Citations

dimensions_citation
42 Dimensions

Readers on

mendeley
83 Mendeley
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Title
Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents
Published in
Breast Cancer Research, April 2015
DOI 10.1186/s13058-015-0564-5
Pubmed ID
Authors

Christy C Ong, Sarah Gierke, Cameron Pitt, Meredith Sagolla, Christine K Cheng, Wei Zhou, Adrian M Jubb, Laura Strickland, Maike Schmidt, Sergio G Duron, David A Campbell, Wei Zheng, Seameen Dehdashti, Min Shen, Nora Yang, Mark L Behnke, Wenwei Huang, John C McKew, Jonathan Chernoff, William F Forrest, Peter M Haverty, Suet-Feung Chin, Emad A Rakha, Andrew R Green, Ian O Ellis, Carlos Caldas, Thomas O’Brien, Lori S Friedman, Hartmut Koeppen, Joachim Rudolph, Klaus P Hoeflich

Abstract

Breast cancer, the most common cause of cancer-related deaths worldwide among women, is a molecularly and clinically heterogeneous disease. Extensive genetic and epigenetic profiling of breast tumors has recently revealed novel putative driver genes, including p21-activated kinase 1 (PAK1). PAK1 is a serine/threonine kinase downstream of small GTP-binding proteins, Rac1 and Cdc42, and is an integral component of growth factor signaling networks and cellular functions fundamental to tumorigenesis. PAK1 dysregulation (copy number gain, mRNA and protein expression) was evaluated in two cohorts of breast cancer tissues (n = 980 and 1108). A novel small molecule inhibitor, FRAX1036, and RNA interference were used to examine PAK1 loss of function and combination with docetaxel in vitro. Mechanism of action for the therapeutic combination, both cellular and molecular, was assessed via time-lapse microscopy and immunoblotting. We demonstrate that focal genomic amplification and over-expression of PAK1 are associated with poor clinical outcome in the luminal subtype of breast cancer (P = 1.29 x 10(-4) and P = 0.015, respectively). Given the role for PAK1 in regulating cytoskeletal organization, we hypothesized that combination of PAK1 inhibition with taxane treatment could be combined to further interfere with microtubule dynamics and cell survival. Consistent with this, administration of docetaxel with either a novel small molecule inhibitor of group I PAKs, FRAX1036, or PAK1 small interfering RNA oligonucleotides dramatically altered signaling to cytoskeletal-associated proteins, such as stathmin, and induced microtubule disorganization and cellular apoptosis. Live-cell imaging revealed that the duration of mitotic arrest mediated by docetaxel was significantly reduced in the presence of FRAX1036, and this was associated with increased kinetics of apoptosis. Taken together, these findings further support PAK1 as a potential target in breast cancer and suggest combination with taxanes as a viable strategy to increase anti-tumor efficacy.

Twitter Demographics

The data shown below were collected from the profiles of 6 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 83 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 1%
India 1 1%
United States 1 1%
Sweden 1 1%
Unknown 79 95%

Demographic breakdown

Readers by professional status Count As %
Researcher 17 20%
Other 16 19%
Student > Ph. D. Student 13 16%
Student > Bachelor 8 10%
Student > Doctoral Student 6 7%
Other 14 17%
Unknown 9 11%
Readers by discipline Count As %
Agricultural and Biological Sciences 30 36%
Biochemistry, Genetics and Molecular Biology 15 18%
Medicine and Dentistry 10 12%
Chemistry 7 8%
Pharmacology, Toxicology and Pharmaceutical Science 5 6%
Other 5 6%
Unknown 11 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 7. 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 21 November 2016.
All research outputs
#2,149,500
of 12,786,839 outputs
Outputs from Breast Cancer Research
#345
of 1,448 outputs
Outputs of similar age
#44,974
of 225,992 outputs
Outputs of similar age from Breast Cancer Research
#3
of 9 outputs
Altmetric has tracked 12,786,839 research outputs across all sources so far. Compared to these this one has done well and is in the 83rd percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,448 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.0. This one has done well, scoring higher than 76% of its peers.
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 225,992 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 80% of its contemporaries.
We're also able to compare this research output to 9 others from the same source and published within six weeks on either side of this one. This one has scored higher than 6 of them.