Home LiteratureArticle Details
PMID: 19147559 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells.

Cancer research ·Vol. 69 ·No. 2 ·2009-01-15 ·Pages 466-74

Luo M, Fan H, Nagy T, Wei H, Wang C, Liu S, Wicha MS, Guan JL

Abstract

Focal adhesion kinase (FAK) has been implicated in the development of cancers, including those of the breast. Nevertheless, the molecular and cellular mechanisms by which FAK promotes mammary tumorigenesis in vivo are not well understood. Here, we show that targeted deletion of FAK in mouse mammary epithelium significantly suppresses mammary tumorigenesis in a well-characterized breast cancer model. Ablation of FAK leads to the depletion of a subset of bipotent cells in the tumor that express both luminal marker keratin 8/18 and basal marker keratin 5. Using mammary stem/progenitor markers, including aldehyde dehydrogenase, CD24, CD29, and CD61, we further revealed that ablation of FAK reduced the pool of cancer stem/progenitor cells in primary tumors of FAK-targeted mice and impaired their self-renewal and migration in vitro. Finally, through transplantation in NOD-SCID mice, we found that cancer stem/progenitor cells isolated from FAK-targeted mice have compromised tumorigenicity and impaired maintenance in vivo. Together, these results show a novel function of FAK in maintaining the mammary cancer stem/progenitor cell population and provide a novel mechanism by which FAK may promote breast cancer development and progression.

MeSH Terms
Aldehyde Dehydrogenase/biosynthesis Animals Cell Movement/physiology Cell Transformation, Neoplastic/metabolism,pathology Epithelial Cells/pathology Female Focal Adhesion Kinase 1/deficiency Mammary Glands, Animal/enzymology,pathology Mammary Neoplasms, Experimental/enzymology,pathology Mice Mice, Inbred NOD Mice, Knockout Mice, SCID Mice, Transgenic Neoplastic Stem Cells/enzymology,pathology
Chemicals
Aldehyde Dehydrogenase Focal Adhesion Kinase 1 Ptk2 protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Luo Ming
Department of Internal Medicine, Division of Molecular Medicine and Genetics, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Fan Huaping
Nagy Tamas
Wei Huijun
Wang Chenran
Liu Suling
Wicha Max S
Guan Jun-Lin
References (50)
50 references, click to expand
  1. Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction.
    Cancer Cell. 2004 Aug;6(2):159-70 PMID: 15324699
  2. Focal adhesion kinase: in command and control of cell motility.
    Nat Rev Mol Cell Biol. 2005 Jan;6(1):56-68 PMID: 15688067
  3. Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis.
    J Cell Biol. 2005 Jun 20;169(6):941-52 PMID: 15967814
  4. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
    Nat Med. 1997 Jul;3(7):730-7 PMID: 9212098
  5. Purification and unique properties of mammary epithelial stem cells.
    Nature. 2006 Feb 23;439(7079):993-7 PMID: 16395311
  6. Identification of p130Cas as a mediator of focal adhesion kinase-promoted cell migration.
    J Cell Biol. 1998 Jan 12;140(1):211-21 PMID: 9425168
  7. Requirement for focal adhesion kinase in the early phase of mammary adenocarcinoma lung metastasis formation.
    Cancer Res. 2005 Jun 1;65(11):4698-706 PMID: 15930288
  8. Transcriptional activation of cyclin D1 promoter by FAK contributes to cell cycle progression.
    Mol Biol Cell. 2001 Dec;12(12):4066-77 PMID: 11739801
  9. Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors.
    Cancer Res. 2008 May 1;68(9):3243-50 PMID: 18451150
  10. Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes.
    Clin Cancer Res. 2000 Jun;6(6):2417-23 PMID: 10873094
  11. Cancer stem cells: an old idea--a paradigm shift.
    Cancer Res. 2006 Feb 15;66(4):1883-90; discussion 1895-6 PMID: 16488983
  12. Crossing paths with Notch in the hyper-network.
    Curr Opin Cell Biol. 2007 Apr;19(2):166-75 PMID: 17317139
  13. Control of adhesion-dependent cell survival by focal adhesion kinase.
    J Cell Biol. 1996 Aug;134(3):793-9 PMID: 8707856
  14. Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology.
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14821-6 PMID: 9843973
  15. Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice.
    Proc Natl Acad Sci U S A. 2008 May 6;105(18):6638-43 PMID: 18448675
  16. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer.
    Cancer Res. 2008 Jun 15;68(12):4674-82 PMID: 18559513
  17. Pyk2 and Src-family protein-tyrosine kinases compensate for the loss of FAK in fibronectin-stimulated signaling events but Pyk2 does not fully function to enhance FAK- cell migration.
    EMBO J. 1998 Oct 15;17(20):5933-47 PMID: 9774338
  18. Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas.
    Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10678-82 PMID: 7479864
  19. Mammary epithelial-specific deletion of the focal adhesion kinase gene leads to severe lobulo-alveolar hypoplasia and secretory immaturity of the murine mammary gland.
    J Biol Chem. 2007 Oct 26;282(43):31766-76 PMID: 17716968
  20. Prospective identification of tumorigenic breast cancer cells.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8 PMID: 12629218
  21. Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression.
    Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20302-7 PMID: 18056629
  22. Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors.
    Cancer Res. 1995 Jul 1;55(13):2752-5 PMID: 7796399
  23. Cancer stem cells: models and concepts.
    Annu Rev Med. 2007;58:267-84 PMID: 17002552
  24. Upregulation of focal adhesion kinase (FAK) expression in ductal carcinoma in situ (DCIS) is an early event in breast tumorigenesis.
    Breast Cancer Res Treat. 2004 Nov;88(2):109-16 PMID: 15564794
  25. Modelling breast cancer: one size does not fit all.
    Nat Rev Cancer. 2007 Sep;7(9):659-72 PMID: 17721431
  26. Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model.
    Oncogene. 2006 Jul 27;25(32):4429-40 PMID: 16547501
  27. Steroid hormone receptor status of mouse mammary stem cells.
    J Natl Cancer Inst. 2006 Jul 19;98(14):1011-4 PMID: 16849684
  28. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.
    Cell Stem Cell. 2007 Nov;1(5):555-67 PMID: 18371393
  29. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis.
    Cell. 2006 Aug 11;126(3):489-502 PMID: 16901783
  30. High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype.
    Mod Pathol. 2005 Oct;18(10):1289-94 PMID: 15861214
  31. Beta1 integrin deletion from the basal compartment of the mammary epithelium affects stem cells.
    Nat Cell Biol. 2008 Jun;10(6):716-22 PMID: 18469806
  32. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model.
    Cancer Cell. 2008 Feb;13(2):141-52 PMID: 18242514
  33. An entire functional mammary gland may comprise the progeny from a single cell.
    Development. 1998 May;125(10):1921-30 PMID: 9550724
  34. Focal adhesion kinase and p53 signaling in cancer cells.
    Int Rev Cytol. 2007;263:103-53 PMID: 17725966
  35. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases.
    Am J Pathol. 2003 Nov;163(5):2113-26 PMID: 14578209
  36. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties.
    Cancer Res. 2005 Jul 1;65(13):5506-11 PMID: 15994920
  37. The Hedgehog response network: sensors, switches, and routers.
    Science. 2004 Jun 18;304(5678):1755-9 PMID: 15205520
  38. Wnt signalling in stem cells and cancer.
    Nature. 2005 Apr 14;434(7035):843-50 PMID: 15829953
  39. Focal adhesion kinase: the first ten years.
    J Cell Sci. 2003 Apr 15;116(Pt 8):1409-16 PMID: 12640026
  40. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease.
    Mol Cell Biol. 1992 Mar;12(3):954-61 PMID: 1312220
  41. Generation of a functional mammary gland from a single stem cell.
    Nature. 2006 Jan 5;439(7072):84-8 PMID: 16397499
  42. The role of focal-adhesion kinase in cancer - a new therapeutic opportunity.
    Nat Rev Cancer. 2005 Jul;5(7):505-15 PMID: 16069815
  43. Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression.
    Genes Dev. 2004 Dec 15;18(24):2998-3003 PMID: 15601818
  44. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells.
    Genes Dev. 2003 May 15;17(10):1253-70 PMID: 12756227
  45. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion.
    Oncogene. 2008 Oct 16;27(47):6120-30 PMID: 18591932
  46. Mammary stem cells and mammopoiesis.
    Cancer Res. 2006 Oct 15;66(20):9798-801 PMID: 17047038
  47. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation.
    Nat Cell Biol. 2007 Feb;9(2):201-9 PMID: 17187062
  48. Diverse mechanisms regulate stem cell self-renewal.
    Curr Opin Cell Biol. 2004 Dec;16(6):700-7 PMID: 15530784
  49. Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors.
    Oncogene. 2006 Sep 28;25(44):5969-84 PMID: 16682956
  50. The properties of a mammary gland cancer stem cell.
    Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10476-81 PMID: 17566110
Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-08-3078
Published
2009-01-15
Pages
466-74
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC3039129
Subset
IM
Grants
NCI NIH HHS · R01 CA101860-05 · United States
NIGMS NIH HHS · R01 GM048050-17 · United States
NCI NIH HHS · R01 CA129765 · United States
NCI NIH HHS · R01 CA101860-06 · United States
NCI NIH HHS · R01 CA101860 · United States
NIGMS NIH HHS · R01 GM048050 · United States
NCI NIH HHS · R01 CA129765-04 · United States
NIGMS NIH HHS · GM48050 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-08-3078 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2