title: Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells.
abstract: The epithelial-mesenchymal transition program becomes activated during malignant progression and can enrich for cancer stem cells (CSCs). We report that inhibition of protein kinase C α (PKCα) specifically targets CSCs but has little effect on non-CSCs. The formation of CSCs from non-stem cells involves a shift from EGFR to PDGFR signaling and results in the PKCα-dependent activation of FRA1. We identified an AP-1 molecular switch in which c-FOS and FRA1 are preferentially utilized in non-CSCs and CSCs, respectively. PKCα and FRA1 expression is associated with the aggressive triple-negative breast cancers, and the depletion of FRA1 results in a mesenchymal-epithelial transition. Hence, identifying molecular features that shift between cell states can be exploited to target signaling components critical to CSCs.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; MIT Ludwig Center for Molecular Oncology, Cambridge, MA 02139, USA.
authors.forename: Wai Leong
authors.initials: WL
authors.lastname: Tam
authors.forename: Haihui
authors.initials: H
authors.lastname: Lu
authors.forename: Joyce
authors.initials: J
authors.lastname: Buikhuisen
authors.forename: Boon Seng
authors.initials: BS
authors.lastname: Soh
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.forename: Zhenhua Jeremy
authors.initials: ZJ
authors.lastname: Wu
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Krall
authors.forename: Brian
authors.initials: B
authors.lastname: Bierie
authors.forename: Wenjun
authors.initials: W
authors.lastname: Guo
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Xiaole Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D051571:Protein Kinase C-alpha; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D017479:Receptors, Platelet-Derived Growth Factor; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D000099169:Fos-Related Antigen 1
references.citation: Nat Rev Cancer. 2007 Apr;7(4):281-94
references.pmid: 17384583
references.citation: Nat Rev Cancer. 2012 May 11;12(6):425-36
references.pmid: 22576165
references.citation: Cancer Res. 2005 Oct 15;65(20):9455-62
references.pmid: 16230409
references.citation: Cell Stem Cell. 2007 Nov;1(5):555-67
references.pmid: 18371393
references.citation: Mol Cancer. 2010 Apr 14;9:76
references.pmid: 20398285
references.citation: Cancer Cell. 2012 Dec 11;22(6):725-36
references.pmid: 23201165
references.citation: Cell. 2009 Nov 25;139(5):871-90
references.pmid: 19945376
references.citation: Nature. 1993 Jul 15;364(6434):249-52
references.pmid: 8321321
references.citation: Cancer Cell. 2006 Dec;10(6):515-27
references.pmid: 17157791
references.citation: Mol Cancer Ther. 2007 Feb;6(2):532-41
references.pmid: 17308052
references.citation: Oncogene. 1991 Dec;6(12):2179-85
references.pmid: 1766667
references.citation: Cancer Cell. 2012 Dec 11;22(6):709-24
references.pmid: 23201163
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Cell. 2009 Aug 21;138(4):645-659
references.pmid: 19682730
references.citation: Cancer Res. 2008 Feb 15;68(4):989-97
references.pmid: 18281472
references.citation: J Pathol. 2010 Aug;221(4):452-61
references.pmid: 20593485
references.citation: Clin Exp Metastasis. 2008;25(6):629-42
references.pmid: 18461285
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references.pmid: 12629218
references.citation: Nat Rev Clin Oncol. 2010 Dec;7(12):683-92
references.pmid: 20877296
references.citation: Nat Struct Mol Biol. 2009 Jun;16(6):624-30
references.pmid: 19465915
references.citation: Annu Rev Med. 2007;58:267-84
references.pmid: 17002552
references.citation: J Clin Invest. 2012 May;122(5):1849-68
references.pmid: 22505459
references.citation: Chem Rev. 2001 Aug;101(8):2353-64
references.pmid: 11749377
references.citation: Cancer Cell. 2007 Mar;11(3):259-73
references.pmid: 17349583
references.citation: J Biol Chem. 2011 Aug 19;286(33):28922-28930
references.pmid: 21715334
references.citation: Annu Rev Cell Dev Biol. 2011;27:347-76
references.pmid: 21740232
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13820-5
references.pmid: 19666588
references.citation: Sci Signal. 2011 Jun 14;4(177):ra41
references.pmid: 21673316
references.citation: Cell. 2011 Jun 10;145(6):926-40
references.pmid: 21663795
references.citation: Curr Opin Biotechnol. 2007 Oct;18(5):460-6
references.pmid: 18023337
references.citation: Annu Rev Biochem. 2001;70:281-312
references.pmid: 11395409
references.citation: Biotechnol Adv. 2012 Nov-Dec;30(6):1662-72
references.pmid: 22841933
references.citation: Cell. 2010 Jan 8;140(1):62-73
references.pmid: 20074520
references.citation: Nat Rev Cancer. 2003 Nov;3(11):859-68
references.pmid: 14668816
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5490-5
references.pmid: 16569692
references.citation: PLoS One. 2008 Aug 06;3(8):e2888
references.pmid: 18682804
references.citation: J Biol Chem. 2002 Jun 28;277(26):23216-22
references.pmid: 11940581
references.citation: Oncogene. 1994 Sep;9(9):2537-47
references.pmid: 8058317