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Title: MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib.
Austin Authors: Young, Adelaide I J;Law, Andrew M K;Castillo, Lesley;Chong, Sabrina;Cullen, Hayley D;Koehler, Martin;Herzog, Sebastian;Brummer, Tilman;Lee, Erinna F;Fairlie, Walter Douglas ;Lucas, Morghan C;Herrmann, David;Allam, Amr;Timpson, Paul;Watkins, D Neil;Millar, Ewan K A;O'Toole, Sandra A;Gallego-Ortega, David;Ormandy, Christopher J;Oakes, Samantha R
Affiliation: St. Vincent's Clinical School, UNSW Medicine, Victoria Street, Darlinghurst, NSW, 2052, Australia
Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
Centre for Biological Systems Analysis (ZBSA) and Centre for Biological Signallling Studies, Albert-Ludwigs-University, Stefan-Meier-Strasse 17, 79104, Freiburg, Germany
Spemann Graduate School for Biology and Medicine and Faculty of Biology, Albert-Ludwigs-University, Stefan-Meier-Strasse 17, 79104, Freiburg, Germany
BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestrasse 18, 79104, Freiburg, Germany
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine and Department of Chemistry and Physics, La Trobe University, Melbourne, Victoria, 3086, Australia
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, 3052, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia
Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Hospital, Grey St, Kogarah, NSW, 2217, Australia
Sydney Medical School, Sydney University, Fisher Rd, Camperdown, NSW, 2006, Australia
Department of Tissue, Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, 2050, NSW, Australia
Issue Date: 2016
Date: 2016-12-08
Publication information: Breast cancer research : BCR 2016; 18(1): 125
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.
DOI: 10.1186/s13058-016-0781-6
Journal: Breast cancer research : BCR
PubMed URL: 27931239
Type: Journal Article
Subjects: BH3 mimetics
Breast cancer
Myeloid cell leukemia-1
SRC family kinase
Appears in Collections:Journal articles

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