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Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: therapeutic implications

Overview of attention for article published in Breast Cancer Research, February 2016
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  • Above-average Attention Score compared to outputs of the same age (64th percentile)

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6 X users

Citations

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23 Dimensions

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59 Mendeley
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Title
Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: therapeutic implications
Published in
Breast Cancer Research, February 2016
DOI 10.1186/s13058-016-0686-4
Pubmed ID
Authors

Muhammad Hasan Bashari, Fengjuan Fan, Sonia Vallet, Martin Sattler, Melissa Arn, Claudia Luckner-Minden, Henning Schulze-Bergkamen, Inka Zörnig, Frederik Marme, Andreas Schneeweiss, Michael H. Cardone, Joseph T. Opferman, Dirk Jäger, Klaus Podar

Abstract

Molecular mechanisms leading to the adaptation of breast cancer (BC) cells to hypoxia are largely unknown. The anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) is frequently amplified in BC; and elevated Mcl-1 levels have been correlated with poor prognosis. Here we investigated the pathophysiologic role of Mcl-1 in Her2-positive BC cells under hypoxic conditions. RNA interference and a novel small molecule inhibitor, EU-5346, were used to examine the role of Mcl-1 in Her2-positive BC cell lines and primary BC cells (sensitive or intrinsically resistant to Her2 inhibitors) under hypoxic conditions (using a hypoxic incubation chamber). Mechanisms-of-action were investigated by RT-PCR, mitochondrial isolation, as well as immunoprecipitation/blotting analysis, and microscopy. The specificity against Mcl-1 of the novel small molecule inhibitor EU5346 was verified in Mcl-1(Δ/null) versus Mcl-1(wt/wt) Murine Embryonic Fibroblasts (MEFs). Proliferation, survival, and spheroid formation were assessed in response to Mcl-1 and Her2 inhibition. We demonstrate for a strong correlation between high Mcl-1 protein levels and hypoxia, predominantly in Her2-positive BC cells. Surprisingly, genetic depletion of Mcl-1 decreased Her2 and Hif-1α levels followed by inhibition of BC cell survival. In contrast, Mcl-1 protein levels were not downregulated after genetic depletion of Her2 indicating a regulatory role of Mcl-1 upstream of Her2. Indeed, Mcl-1 and Her2 co-localize within the mitochondrial fraction and form a Mcl-1/Her2- protein complex. Similar to genetically targeting Mcl-1 the novel small molecule Mcl-1 inhibitor EU-5346 induced cell death and decreased spheroid formation in Her2-positive BC cells. Of interest, EU-5346 induced ubiquitination of Mcl-1- bound Her2 demonstrating a previously unknown role for Mcl-1 to stabilize Her2 protein levels. Importantly, targeting Mcl-1 was also active in Her2-positive BC cells resistant to Her2 inhibitors, including a brain-primed Her2-positive cell line. Our data demonstrate a critical role of Mcl-1 in Her2-positive BC cell survival under hypoxic conditions and provide the preclinical framework for the therapeutic use of novel Mcl-1- targeting agents to improve patient outcome in BC.

X Demographics

X Demographics

The data shown below were collected from the profiles of 6 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 59 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 59 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 11 19%
Researcher 9 15%
Student > Master 7 12%
Student > Bachelor 5 8%
Other 3 5%
Other 11 19%
Unknown 13 22%
Readers by discipline Count As %
Medicine and Dentistry 14 24%
Biochemistry, Genetics and Molecular Biology 14 24%
Agricultural and Biological Sciences 4 7%
Pharmacology, Toxicology and Pharmaceutical Science 4 7%
Nursing and Health Professions 1 2%
Other 5 8%
Unknown 17 29%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 4. 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 02 March 2016.
All research outputs
#8,454,712
of 25,387,480 outputs
Outputs from Breast Cancer Research
#964
of 2,050 outputs
Outputs of similar age
#110,244
of 308,238 outputs
Outputs of similar age from Breast Cancer Research
#26
of 32 outputs
Altmetric has tracked 25,387,480 research outputs across all sources so far. This one has received more attention than most of these and is in the 66th percentile.
So far Altmetric has tracked 2,050 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 12.1. This one has gotten more attention than average, scoring higher than 52% 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 308,238 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 64% of its contemporaries.
We're also able to compare this research output to 32 others from the same source and published within six weeks on either side of this one. This one is in the 21st percentile – i.e., 21% of its contemporaries scored the same or lower than it.