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PMID: 17875704 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

Transforming growth factor-beta can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model.

Cancer research ·Vol. 67 ·No. 18 ·2007-09-15 ·Pages 8643-52

Tang B, Yoo N, Vu M, Mamura M, Nam JS, Ooshima A, Du Z, Desprez PY, Anver MR, Michalowska AM, Shih J, Parks WT, Wakefield LM

Abstract

The transforming growth factor-beta (TGF-beta) pathway has tumor-suppressor activity in many epithelial tissues. Because TGF-beta is a potent inhibitor of epithelial cell proliferation, it has been widely assumed that this property underlies the tumor-suppressor effect. Here, we have used a xenograft model of breast cancer to show that endogenous TGF-beta has the potential to suppress tumorigenesis through a novel mechanism, involving effects at two distinct levels in the hierarchy of cellular progeny that make up the epithelial component of the tumor. First, TGF-beta reduces the size of the putative cancer stem or early progenitor cell population, and second it promotes differentiation of a more committed, but highly proliferative, progenitor cell population to an intrinsically less proliferative state. We further show that reduced expression of the type II TGF-beta receptor correlates with loss of luminal differentiation in a clinical breast cancer cohort, suggesting that this mechanism may be clinically relevant. At a molecular level, the induction of differentiation by TGF-beta involves down-regulation of Id1, and forced overexpression of Id1 can promote tumorigenesis despite persistence of the antiproliferative effect of TGF-beta. These data suggest new roles for the TGF-beta pathway in regulating tumor cell dynamics that are independent of direct effects on proliferation.

MeSH Terms
Animals Breast Neoplasms/genetics,metabolism,pathology Cell Differentiation/physiology Cell Line, Tumor Down-Regulation Female Gene Expression Profiling Humans Inhibitor of Differentiation Protein 1/biosynthesis,genetics Mice Mice, Nude Neoplasm Transplantation Neoplastic Stem Cells/metabolism,pathology Protein Serine-Threonine Kinases/biosynthesis,deficiency Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta/biosynthesis,deficiency Transforming Growth Factor beta/deficiency,physiology Transplantation, Heterologous
Chemicals
ID1 protein, human Inhibitor of Differentiation Protein 1 Receptors, Transforming Growth Factor beta Transforming Growth Factor beta Protein Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Tang Binwu
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.
Yoo Naomi
Vu Mary
Mamura Mizuko
Nam Jeong-Seok
Ooshima Akira
Du Zhijun
Desprez Pierre-Yves
Anver Miriam R
Michalowska Aleksandra M
Shih Joanna
Parks W Tony
Wakefield Lalage M
References (50)
50 references, click to expand
  1. Transforming growth factor-beta and breast cancer risk in women with mammary epithelial hyperplasia.
    J Natl Cancer Inst. 1999 Dec 15;91(24):2096-101 PMID: 10601380
  2. Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15.
    Nature. 1997 May 22;387(6631):417-22 PMID: 9163429
  3. A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer cells.
    Cancer Res. 2000 Mar 1;60(5):1332-40 PMID: 10728695
  4. ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis.
    J Cell Sci. 2000 Nov;113 ( Pt 22):3897-905 PMID: 11058077
  5. Progression of premalignant MCF10AT generates heterogeneous malignant variants with characteristic histologic types and immunohistochemical markers.
    Breast Cancer Res Treat. 2000 Dec;64(3):235-40 PMID: 11200773
  6. Malignant MCF10CA1 cell lines derived from premalignant human breast epithelial MCF10AT cells.
    Breast Cancer Res Treat. 2001 Jan;65(2):101-10 PMID: 11261825
  7. c-Myc activation in transgenic mouse epidermis results in mobilization of stem cells and differentiation of their progeny.
    Curr Biol. 2001 Apr 17;11(8):558-68 PMID: 11369200
  8. Reducing mammary cancer risk through premature stem cell senescence.
    Oncogene. 2001 Apr 26;20(18):2264-72 PMID: 11402321
  9. Transgenic mice overexpressing a dominant-negative mutant type II transforming growth factor beta receptor show enhanced tumorigenesis in the mammary gland and lung in response to the carcinogen 7,12-dimethylbenz-[a]-anthracene.
    Cancer Res. 1997 Dec 15;57(24):5564-70 PMID: 9407968
  10. Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis.
    Cancer Res. 1999 Jul 15;59(14):3379-86 PMID: 10416598
  11. G1 cell-cycle control and cancer.
    Nature. 2004 Nov 18;432(7015):298-306 PMID: 15549091
  12. The mammary gland "side population": a putative stem/progenitor cell marker?
    J Mammary Gland Biol Neoplasia. 2005 Jan;10(1):37-47 PMID: 15886885
  13. Basal cytokeratins and their relationship to the cellular origin and functional classification of breast cancer.
    Breast Cancer Res. 2005;7(4):143-8 PMID: 15987465
  14. 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
  15. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic.
    Cancer Res. 2005 Jul 15;65(14):6207-19 PMID: 16024622
  16. Id family of helix-loop-helix proteins in cancer.
    Nat Rev Cancer. 2005 Aug;5(8):603-14 PMID: 16034366
  17. Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines.
    Cancer Res. 2005 Oct 1;65(19):8944-50 PMID: 16204067
  18. Transforming growth factor-beta signaling in stem cells and cancer.
    Science. 2005 Oct 7;310(5745):68-71 PMID: 16210527
  19. Generation of a functional mammary gland from a single stem cell.
    Nature. 2006 Jan 5;439(7072):84-8 PMID: 16397499
  20. Stem cells in the etiology and treatment of cancer.
    Curr Opin Genet Dev. 2006 Feb;16(1):60-4 PMID: 16377171
  21. Cancer stem cells: an old idea--a paradigm shift.
    Cancer Res. 2006 Feb 15;66(4):1883-90; discussion 1895-6 PMID: 16488983
  22. Purification and unique properties of mammary epithelial stem cells.
    Nature. 2006 Feb 23;439(7079):993-7 PMID: 16395311
  23. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes.
    Cancer Cell. 2006 Dec;10(6):515-27 PMID: 17157791
  24. Cancer stem cells: models and concepts.
    Annu Rev Med. 2007;58:267-84 PMID: 17002552
  25. Aberrant function of the Ras signal transduction pathway in human breast cancer.
    Breast Cancer Res Treat. 1995 Jul;35(1):133-44 PMID: 7612899
  26. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype.
    Nat Med. 2001 Sep;7(9):1028-34 PMID: 11533706
  27. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
    Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74 PMID: 11553815
  28. TGF-beta signaling in tumor suppression and cancer progression.
    Nat Genet. 2001 Oct;29(2):117-29 PMID: 11586292
  29. Consequences of altered TGF-beta expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects.
    Oncogene. 2002 Jan 3;21(1):108-18 PMID: 11791181
  30. "Stemness": transcriptional profiling of embryonic and adult stem cells.
    Science. 2002 Oct 18;298(5593):597-600 PMID: 12228720
  31. Overexpression of Id-1 is associated with poor clinical outcome in node negative breast cancer.
    Int J Cancer. 2003 May 10;104(6):677-82 PMID: 12640673
  32. A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells.
    Mol Cell. 2003 Apr;11(4):915-26 PMID: 12718878
  33. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells.
    Genes Dev. 2003 May 15;17(10):1253-70 PMID: 12756227
  34. Repeated observation of breast tumor subtypes in independent gene expression data sets.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23 PMID: 12829800
  35. Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation.
    Am J Pathol. 2003 Oct;163(4):1539-49 PMID: 14507660
  36. Evidence of progenitor cells of glandular and myoepithelial cell lineages in the human adult female breast epithelium: a new progenitor (adult stem) cell concept.
    Cell Prolif. 2003 Oct;36 Suppl 1:73-84 PMID: 14521517
  37. TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression.
    J Clin Invest. 2003 Oct;112(7):1116-24 PMID: 14523048
  38. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3.
    Cell. 2003 Oct 31;115(3):281-92 PMID: 14636556
  39. Defining the epithelial stem cell niche in skin.
    Science. 2004 Jan 16;303(5656):359-63 PMID: 14671312
  40. Histologically normal human mammary epithelia with silenced p16(INK4a) overexpress COX-2, promoting a premalignant program.
    Cancer Cell. 2004 Mar;5(3):263-73 PMID: 15050918
  41. Gene expression analysis in SV40-immortalized human breast luminal epithelial cells with stem cell characteristics using a cDNA microarray.
    Int J Oncol. 2004 Jun;24(6):1545-58 PMID: 15138599
  42. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.
    Nat Genet. 2004 Oct;36(10):1117-21 PMID: 15378062
  43. A distinct "side population" of cells with high drug efflux capacity in human tumor cells.
    Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14228-33 PMID: 15381773
  44. Increased secretion of type beta transforming growth factor accompanies viral transformation of cells.
    Mol Cell Biol. 1985 Jan;5(1):242-7 PMID: 3856735
  45. Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium.
    Cell Growth Differ. 1990 Apr;1(4):161-70 PMID: 1707299
  46. Ectopic TGF beta 1 expression in the secretory mammary epithelium induces early senescence of the epithelial stem cell population.
    Dev Biol. 1995 Mar;168(1):47-61 PMID: 7883078
  47. Mammary tumor suppression by transforming growth factor beta 1 transgene expression.
    Proc Natl Acad Sci U S A. 1995 May 9;92(10):4254-8 PMID: 7753792
  48. Suppression of mammary epithelial cell differentiation by the helix-loop-helix protein Id-1.
    Mol Cell Biol. 1995 Jun;15(6):3398-404 PMID: 7760836
  49. MCF10AT: a model for the evolution of cancer from proliferative breast disease.
    Am J Pathol. 1996 Jan;148(1):313-9 PMID: 8546221
  50. Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in-situ and invasive carcinomas.
    Histopathology. 2000 Feb;36(2):168-77 PMID: 10672063
Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-07-0982
Published
2007-09-15
Pages
8643-52
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC2427144
Subset
IM
Grants
Intramural NIH HHS · Z01 BC005785-12 · United States
NCI NIH HHS · N01-CO-12400 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-07-0982 PMC Full Text View journal details
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