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

Young, AIJ; Law, AMK; Castillo, L; Chong, S; Cullen, HD; Koehler, M; Herzog, S; Brummer, T; Lee, EF; Fairlie, WD; Lucas, MC; Herrmann, D; Allam, A; Timpson, P; Watkins, DN; Millar, EKA; O'Toole, SA; Gallego-Ortega, D; Ormandy, CJ; Oakes, SR

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

Young, AIJ Law, AMK Castillo, L Chong, S Cullen, HD Koehler, M Herzog, S Brummer, T Lee, EF Fairlie, WD Lucas, MC Herrmann, D Allam, A Timpson, P Watkins, DN Millar, EKA O'Toole, SA Gallego-Ortega, D Ormandy, CJ Oakes, SR

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Publisher:: BMC
Publication Type:: Journal Article
Citation:: Breast Cancer Res, 2016, 18, (1), pp. 125
Issue Date:: 2016-12-08

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Field	Value	Language
dc.contributor.author	Young, AIJ
dc.contributor.author	Law, AMK
dc.contributor.author	Castillo, L
dc.contributor.author	Chong, S
dc.contributor.author	Cullen, HD
dc.contributor.author	Koehler, M
dc.contributor.author	Herzog, S
dc.contributor.author	Brummer, T
dc.contributor.author	Lee, EF
dc.contributor.author	Fairlie, WD
dc.contributor.author	Lucas, MC
dc.contributor.author	Herrmann, D
dc.contributor.author	Allam, A
dc.contributor.author	Timpson, P
dc.contributor.author	Watkins, DN
dc.contributor.author	Millar, EKA
dc.contributor.author	O'Toole, SA
dc.contributor.author	Gallego-Ortega, D
dc.contributor.author	Ormandy, CJ
dc.contributor.author	Oakes, SR
dc.date.accessioned	2022-04-13T12:29:32Z
dc.date.available	2016-11-16
dc.date.available	2022-04-13T12:29:32Z
dc.date.issued	2016-12-08
dc.identifier.citation	Breast Cancer Res, 2016, 18, (1), pp. 125
dc.identifier.issn	1465-5411
dc.identifier.issn	1465-542X
dc.identifier.uri	http://hdl.handle.net/10453/156222
dc.description.abstract	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
dc.format	Electronic
dc.language	eng
dc.publisher	BMC
dc.relation.ispartof	Breast Cancer Res
dc.relation.isbasedon	10.1186/s13058-016-0781-6
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Cell Death
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Movement
dc.subject.mesh	Dasatinib
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Drug Resistance, Neoplasm
dc.subject.mesh	Female
dc.subject.mesh	Gene Expression
dc.subject.mesh	Humans
dc.subject.mesh	Immunohistochemistry
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Mutation
dc.subject.mesh	Myeloid Cell Leukemia Sequence 1 Protein
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Neoplasm Metastasis
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Tumor Burden
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Neoplasm Metastasis
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Tumor Burden
dc.subject.mesh	Immunohistochemistry
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Cell Death
dc.subject.mesh	Cell Movement
dc.subject.mesh	Gene Expression
dc.subject.mesh	Drug Resistance, Neoplasm
dc.subject.mesh	Mutation
dc.subject.mesh	Female
dc.subject.mesh	Myeloid Cell Leukemia Sequence 1 Protein
dc.subject.mesh	Dasatinib
dc.title	MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib.
dc.type	Journal Article
utslib.citation.volume	18
utslib.location.activity	England
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.date.updated	2022-04-13T12:29:25Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	18
utslib.citation.issue	1

Abstract:

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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http://hdl.handle.net/10453/156222