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Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy

Overview of attention for article published in Proceedings of the National Academy of Sciences of the United States of America, February 2018
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (85th percentile)
  • Average Attention Score compared to outputs of the same age and source

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18 X users
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1 patent
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2 Facebook pages

Citations

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58 Mendeley
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Title
Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy
Published in
Proceedings of the National Academy of Sciences of the United States of America, February 2018
DOI 10.1073/pnas.1717820115
Pubmed ID
Authors

Konstantinos V. Floros, Timothy L. Lochmann, Bin Hu, Carles Monterrubio, Mark T. Hughes, Jason D. Wells, Cristina Bernadó Morales, Maninderjit S. Ghotra, Carlotta Costa, Andrew J. Souers, Sosipatros A. Boikos, Joel D. Leverson, Ming Tan, Violeta Serra, Jennifer E. Koblinski, Joaquin Arribas, Aleix Prat, Laia Paré, Todd W. Miller, Mikhail G. Dozmorov, Hisashi Harada, Brad E. Windle, Maurizio Scaltriti, Anthony C. Faber

Abstract

HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors inEGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, inHER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron ofHER2, termedmiR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription ofNOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers likeEGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes.

X Demographics

X Demographics

The data shown below were collected from the profiles of 18 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 58 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 58 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 10 17%
Student > Ph. D. Student 7 12%
Student > Bachelor 6 10%
Student > Postgraduate 5 9%
Student > Master 5 9%
Other 9 16%
Unknown 16 28%
Readers by discipline Count As %
Medicine and Dentistry 15 26%
Biochemistry, Genetics and Molecular Biology 12 21%
Agricultural and Biological Sciences 8 14%
Pharmacology, Toxicology and Pharmaceutical Science 3 5%
Psychology 2 3%
Other 4 7%
Unknown 14 24%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 15. 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 24 December 2020.
All research outputs
#2,273,283
of 24,622,191 outputs
Outputs from Proceedings of the National Academy of Sciences of the United States of America
#26,955
of 101,438 outputs
Outputs of similar age
#47,617
of 335,144 outputs
Outputs of similar age from Proceedings of the National Academy of Sciences of the United States of America
#530
of 1,045 outputs
Altmetric has tracked 24,622,191 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 90th percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 101,438 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 38.8. This one has gotten more attention than average, scoring higher than 73% 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 335,144 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 85% of its contemporaries.
We're also able to compare this research output to 1,045 others from the same source and published within six weeks on either side of this one. This one is in the 49th percentile – i.e., 49% of its contemporaries scored the same or lower than it.