title: Candidate Antimetastasis Drugs Suppress the Metastatic Capacity of Breast Cancer Cells by Reducing Membrane Fluidity.
abstract: Despite the high mortality from metastatic cancer, therapeutic targets to prevent metastasis are limited. Efforts to identify genetic aberrations that predispose tumors to metastasis have been mostly unsuccessful. To understand the nature of candidate targets for metastatic disease, we performed an in silico screen to identify drugs that can inhibit a gene expression signature associated with epithelial-mesenchymal transition (EMT). Compounds discovered through this method, including those previously identified, appeared to restrict metastatic capacity through a common mechanism, the ability to modulate the fluidity of cell membranes. Treatment of breast cancer cell lines with the putative antimetastasis agents reduced membrane fluidity, resulting in decreased cell motility, stem cell-like properties, and EMT in vitro, and the drugs also inhibited spontaneous metastasis in vivo When fluidity was unchanged, the antimetastasis compounds could no longer restrict metastasis, indicating a causal association between fluidity and metastasis. We further demonstrate that fluidity can be regulated by cellular cholesterol flux, as the cholesterol efflux channel ABCA1 potentiated metastatic behaviors in vitro and in vivo The requirement for fluidity was further supported by the finding in breast cancer patients that ABCA1 was overexpressed in 41% of metastatic tumors, reducing time to metastasis by 9 years. Collectively, our findings reveal increased membrane fluidity as a necessary cellular feature of metastatic potential that can be controlled by many currently available drugs, offering a viable therapeutic opportunity to prevent cancer metastasis. Cancer Res; 76(7); 2037-49. ©2016 AACR.
authors.affiliation: Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Weina
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Sara
authors.initials: S
authors.lastname: Prijic
authors.affiliation: Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Bettina C
authors.initials: BC
authors.lastname: Urban
authors.affiliation: Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tisza
authors.affiliation: Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zuo
authors.affiliation: Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas. Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Tan
authors.affiliation: School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
authors.affiliation: Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas. Graduate School of Biomedical Sciences, Houston, Texas. School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas. Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas. Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas. jeffrey.t.chang@uth.tmc.edu.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008560:Membrane Fluidity / Q000235:genetics*
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Nat Chem Biol. 2007 May;3(5):268-73
references.pmid: 17417631
references.citation: J Mammary Gland Biol Neoplasia. 2012 Jun;17(2):111-7
references.pmid: 22665270
references.citation: Invasion Metastasis. 1981;1(2):99-110
references.pmid: 7188384
references.citation: J Cell Physiol. 2011 Sep;226(9):2378-90
references.pmid: 21660961
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11041-8
references.pmid: 10500120
references.citation: J Pharm Sci. 1987 Jan;76(1):25-8
references.pmid: 3585718
references.citation: Cancer Cell. 2002 Sep;2(3):205-16
references.pmid: 12242153
references.citation: Cell. 2004 Jun 25;117(7):927-39
references.pmid: 15210113
references.citation: J Biol Chem. 2012 Nov 2;287(45):37732-44
references.pmid: 22989880
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):27-30
references.pmid: 10592173
references.citation: Science. 2006 Sep 29;313(5795):1929-35
references.pmid: 17008526
references.citation: Mol Oncol. 2007 Jun;1(1):84-96
references.pmid: 18516279
references.citation: Genes Dev. 2001 Jan 1;15(1):50-65
references.pmid: 11156605
references.citation: Sci Rep. 2015 Jun 30;5:11766
references.pmid: 26123483
references.citation: PLoS One. 2012;7(12):e51136
references.pmid: 23251436
references.citation: J Clin Invest. 1999 Oct;104(8):R25-31
references.pmid: 10525055
references.citation: Cell. 2009 Aug 21;138(4):645-659
references.pmid: 19682730
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13253-7
references.pmid: 21788521
references.citation: Mol Carcinog. 2015 Jun;54(6):417-29
references.pmid: 24293234
references.citation: J Lipid Res. 1997 Nov;38(11):2264-72
references.pmid: 9392424
references.citation: Science. 2013 Mar 29;339(6127):1546-58
references.pmid: 23539594
references.citation: Cell Rep. 2012 Sep 27;2(3):580-90
references.pmid: 22981231
references.citation: Bioinformatics. 2006 Dec 1;22(23):2926-33
references.pmid: 17000751
references.citation: PLoS One. 2010 Nov 15;5(11):e13984
references.pmid: 21085593
references.citation: Breast Cancer Res. 2010;12(5):R68
references.pmid: 20813035
references.citation: Cell. 2012 Jun 8;149(6):1284-97
references.pmid: 22632761
references.citation: Gastroenterology. 2006 Sep;131(3):830-40
references.pmid: 16952552
references.citation: Science. 2013 Nov 29;342(6162):1094-8
references.pmid: 24288332
references.citation: Nat Cell Biol. 2000 Feb;2(2):76-83
references.pmid: 10655586
references.citation: Blood. 1978 Dec;52(6):1099-114
references.pmid: 214187
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Arch Biochem Biophys. 2007 Mar 1;459(1):98-106
references.pmid: 17222386
references.citation: PLoS One. 2008 Aug 06;3(8):e2888
references.pmid: 18682804
references.citation: Curr Biol. 1998 Nov 19;8(23):1243-52
references.pmid: 9822576
references.citation: J Biol Chem. 2005 Mar 25;280(12):11740-8
references.pmid: 15647282
references.citation: Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2155-61
references.pmid: 15358601
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15449-54
references.pmid: 20713713
references.citation: Biochemistry. 1987 Mar 24;26(6):1746-56
references.pmid: 3593687
references.citation: J Biol Chem. 2000 Nov 24;275(47):36803-10
references.pmid: 10969078
references.citation: Science. 2011 Mar 25;331(6024):1559-64
references.pmid: 21436443
references.citation: Int J Cancer. 1989 Oct 15;44(4):707-13
references.pmid: 2793242