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MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib

Overview of attention for article published in Breast Cancer Research, December 2016
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Title
MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib
Published in
Breast Cancer Research, December 2016
DOI 10.1186/s13058-016-0781-6
Pubmed ID
Authors

Adelaide I. J. Young, Andrew M. K. Law, Lesley Castillo, Sabrina Chong, Hayley D. Cullen, Martin Koehler, Sebastian Herzog, Tilman Brummer, Erinna F. Lee, Walter D. Fairlie, Morghan C. Lucas, David Herrmann, Amr Allam, Paul Timpson, D. Neil Watkins, Ewan K. A. Millar, Sandra A. O’Toole, David Gallego-Ortega, Christopher J. Ormandy, Samantha R. Oakes

Abstract

Metastatic disease is largely resistant to therapy and accounts for almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator of cell survival and chemo-resistance in a wide range of malignancies, and thus its inhibition may prove to be therapeutically useful. To examine whether targeting MCL-1 may provide an effective treatment for breast cancer, we constructed inducible models of BIMs2A expression (a specific MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDA-MB-231-2A) cells. MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263, demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown in an organotypic model, induction of BIMs2A produced an almost complete suppression of invasion. Apoptosis was induced in such a small proportion of these cells that it could not account for the large decrease in invasion, suggesting that MCL-1 was operating via a previously undetected mechanism. MCL-1 antagonism also suppressed local invasion and distant metastasis to the lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinases and their targets, which suggested that MCL-1 might act as an upstream modulator of invasion via this pathway. Inhibition of MCL-1 in combination with dasatinib suppressed invasion in 3D models of invasion and inhibited the establishment of tumors in vivo. These data provide the first evidence that MCL-1 drives breast cancer cell invasion and suggests that MCL-1 antagonists could be used alone or in combination with drugs targeting Src kinases such as dasatinib to suppress metastasis.

X Demographics

X Demographics

The data shown below were collected from the profiles of 3 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 86 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
France 1 1%
Unknown 85 99%

Demographic breakdown

Readers by professional status Count As %
Student > Master 14 16%
Student > Ph. D. Student 12 14%
Researcher 10 12%
Student > Bachelor 8 9%
Unspecified 7 8%
Other 10 12%
Unknown 25 29%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 24 28%
Pharmacology, Toxicology and Pharmaceutical Science 8 9%
Unspecified 7 8%
Agricultural and Biological Sciences 7 8%
Medicine and Dentistry 6 7%
Other 6 7%
Unknown 28 33%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 3. 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 20 December 2016.
All research outputs
#14,913,296
of 25,371,288 outputs
Outputs from Breast Cancer Research
#1,295
of 2,052 outputs
Outputs of similar age
#219,360
of 420,287 outputs
Outputs of similar age from Breast Cancer Research
#14
of 25 outputs
Altmetric has tracked 25,371,288 research outputs across all sources so far. This one is in the 40th percentile – i.e., 40% of other outputs scored the same or lower than it.
So far Altmetric has tracked 2,052 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 12.2. 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 420,287 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 47th percentile – i.e., 47% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 25 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.