title: MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib.
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.
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Adelaide I J
authors.initials: AI
authors.lastname: Young
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Andrew M K
authors.initials: AM
authors.lastname: Law
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Lesley
authors.initials: L
authors.lastname: Castillo
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Chong
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Hayley D
authors.initials: HD
authors.lastname: Cullen
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Koehler
authors.affiliation: BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestrasse 18, 79104, Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Herzog
authors.affiliation: Centre for Biological Systems Analysis (ZBSA) and Centre for Biological Signallling Studies, 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.
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.affiliation: Olivia Newton-John Cancer Research Institute, 145 Studley Rd, Heidelberg, Victoria, 3084, 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.
authors.forename: Erinna F
authors.initials: EF
authors.lastname: Lee
authors.affiliation: Olivia Newton-John Cancer Research Institute, 145 Studley Rd, Heidelberg, Victoria, 3084, 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.
authors.forename: Walter D
authors.initials: WD
authors.lastname: Fairlie
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Morghan C
authors.initials: MC
authors.lastname: Lucas
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Herrmann
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Amr
authors.initials: A
authors.lastname: Allam
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.|St. Vincent's Clinical School, UNSW Medicine, Victoria Street, Darlinghurst, NSW, 2052, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.|St. Vincent's Clinical School, UNSW Medicine, Victoria Street, Darlinghurst, NSW, 2052, Australia.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Watkins
authors.affiliation: Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Hospital, Grey St, Kogarah, NSW, 2217, Australia.
authors.forename: Ewan K A
authors.initials: EK
authors.lastname: Millar
authors.affiliation: 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.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: O'Toole
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.|St. Vincent's Clinical School, UNSW Medicine, Victoria Street, Darlinghurst, NSW, 2052, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Gallego-Ortega
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.|St. Vincent's Clinical School, UNSW Medicine, Victoria Street, Darlinghurst, NSW, 2052, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ormandy
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia. s.oakes@garvan.org.au.|St. Vincent's Clinical School, UNSW Medicine, Victoria Street, Darlinghurst, NSW, 2052, Australia. s.oakes@garvan.org.au.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Oakes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D000069439:Dasatinib / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D000069439:Dasatinib
keywords: BH3 mimetics; BIMs2A; Breast cancer; Cofilin; Invasion; Metastasis; Myeloid cell leukemia-1; SRC family kinase