Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

Oncogene volume 31, pages 2164–2174 (2012)Cite this article

Abstract

Accumulating evidence suggests that a subpopulation of breast cancer cells, referred to as cancer stem cells (CSCs), have the ability to propagate a tumor and potentially seed new metastases. Furthermore, stimulation of an epithelial-to-mesenchymal transition by factors like transforming growth factor-β (TGFβ) is accompanied with the generation of breast CSCs. Previous observations indicated that bone morphogenetic protein-7 (BMP7) antagonizes the protumorigenic and prometastatic actions of TGFβ, but whether BMP7 action is mechanistically linked to breast CSCs has remained elusive. Here, we have studied the effects of BMP7, BMP2 and a BMP2/7 heterodimer on the formation of human breast CSCs (ALDHhi/CD44hi/CD24−/low) and bone metastases formation in a preclinical model of intra-cardiac injection of MDA-MB-231 cells in athymic nude (Balb/c nu/nu) mice. The BMP2/7 heterodimer was the most efficient stimulator of BMP signaling and very effectively reduced TGFβ-driven Smad signaling and cancer cell invasiveness. The tested BMPs—particularly the heterodimeric BMP2/7—strongly reduced the size of the ALDHhi/CD44hi/CD24−/low CSC subpopulation. In keeping with these in vitro observations, pretreatment of cancer cells with BMPs for 72 h prior to systemic inoculation of the cancer cells inhibited the formation of bone metastases. Collectively, our data support the notion that breast CSCs are involved in bone metastasis formation and describe heterodimeric BMP2/7 as a powerful TGFβ antagonist with anti-metastatic potency.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100: 3983–3988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alison MR, Guppy NJ, Lim SM, Nicholson LJ . (2010). Finding cancer stem cells: are aldehyde dehydrogenases fit for purpose? J Pathol 222: 335–344.

    Article  PubMed  Google Scholar 

  • Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G et al. (2006). Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12: 5615–5621.

    Article  CAS  PubMed  Google Scholar 

  • Buijs JT, Henriquez NV, van Overveld PG, van der Horst G, Que I, Schwaninger R et al. (2007a). Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Cancer Res 67: 8742–8751.

    Article  CAS  PubMed  Google Scholar 

  • Buijs JT, Henriquez NV, van Overveld PG, van der Horst G, ten Dijke P, van der Pluijm G . (2007b). TGF-beta and BMP7 interactions in tumour progression and bone metastasis. Clin Exp Metastasis 24: 609–617.

    Article  CAS  PubMed  Google Scholar 

  • Buijs JT, Rentsch CA, van der Horst G, van Overveld PG, Wetterwald A, Schwaninger R et al. (2007c). BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am J Pathol 171: 1047–1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheung AM, Wan TS, Leung JC, Chan LY, Huang H, Kwong YL et al. (2007). Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD/SCID engrafting potential. Leukemia 21: 1423–1430.

    Article  CAS  PubMed  Google Scholar 

  • Coleman RE . (1997). Skeletal complications of malignancy. Cancer 80: 1588–1594.

    Article  CAS  PubMed  Google Scholar 

  • Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ . (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65: 10946–10951.

    Article  CAS  PubMed  Google Scholar 

  • Cook C, Vezina CM, Allgeier SH, Shaw A, Yu M, Peterson RE et al. (2007). Noggin is required for normal lobe patterning and ductal budding in the mouse prostate. Dev Biol 312: 217–230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A et al. (2009). Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA 106: 13820–13825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Creighton CJ, Chang JC, Rosen JM . (2010). Epithelial–mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J Mammary Gland Biol Neoplasia 15: 253–260.

    Article  PubMed  Google Scholar 

  • Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM . (1998). Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 17: 3091–3100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M et al. (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1: 555–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grishina IB, Kim SY, Ferrara C, Makarenkova HP, Walden PD . (2005). BMP7 inhibits branching morphogenesis in the prostate gland and interferes with Notch signaling. Dev Biol 288: 334–347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hazama M, Aono A, Ueno N, Fujisawa Y . (1995). Efficient expression of a heterodimer of bone morphogenetic protein subunits using a baculovirus expression system. Biochem Biophys Res Commun 209: 859–866.

    Article  CAS  PubMed  Google Scholar 

  • Hollier BG, Evans K, Mani SA . (2009). The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 14: 29–43.

    Article  PubMed  Google Scholar 

  • Israel DI, Nove J, Kerns KM, Kaufman RJ, Rosen V, Cox KA et al. (1996). Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. Growth Factors 13: 291–300.

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Xu J, Ward E . (2010). Cancer statistics, 2010. CA Cancer J Clin 60: 277–300.

    Article  PubMed  Google Scholar 

  • Klose A, Waerzeggers Y, Monfared P, Vukicevic S, Kaijzel EL, Winkeler A et al. (2011). Imaging bone morphogenetic protein 7 induced cell cycle arrest in experimental gliomas. Neoplasia 13: 276–285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koh JT, Zhao Z, Wang Z, Lewis IS, Krebsbach PH, Franceschi RT . (2008). Combinatorial gene therapy with BMP2/7 enhances cranial bone regeneration. J Dent Res 87: 845–849.

    Article  CAS  PubMed  Google Scholar 

  • Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S et al. (2010). Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One 5: e12445.

    Article  PubMed  PubMed Central  Google Scholar 

  • Korchynskyi O, ten Dijke P . (2002). Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem 277: 4883–4891.

    Article  CAS  PubMed  Google Scholar 

  • Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF et al. (2008). Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100: 672–679.

    Article  CAS  PubMed  Google Scholar 

  • Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. (2008). The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133: 704–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Notting IC, Buijs JT, Que I, Mintardjo RE, van der Horst G, Karperien M et al. (2005). Whole-body bioluminescent imaging of human uveal melanoma in a new mouse model of local tumor growth and metastasis. Invest Ophthalmol Vis Sci 46: 1581–1587.

    Article  PubMed  Google Scholar 

  • O'Brien CA, Pollett A, Gallinger S, Dick JE . (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445: 106–110.

    Article  CAS  PubMed  Google Scholar 

  • Petersen M, Pardali E, van der Horst G, Cheung H, van den Hoogen C, van der Pluijm G et al. (2010). Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene 29: 1351–1361.

    Article  CAS  PubMed  Google Scholar 

  • Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G et al. (2006). Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444: 761–765.

    Article  CAS  PubMed  Google Scholar 

  • Polyak K, Weinberg RA . (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9: 265–273.

    Article  CAS  PubMed  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL . (2001). Stem cells, cancer, and cancer stem cells. Nature 414: 105–111.

    Article  CAS  PubMed  Google Scholar 

  • Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature 445: 111–115.

    Article  CAS  PubMed  Google Scholar 

  • Schwaninger R, Rentsch CA, Wetterwald A, van der Horst G, van Bezooijen RL, van der Pluijm G et al. (2007). Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases. Am J Pathol 170: 160–175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J et al. (2007). Molecular definition of breast tumor heterogeneity. Cancer Cell 11: 259–273.

    Article  CAS  PubMed  Google Scholar 

  • Singh A, Settleman J . (2010). EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29: 4741–4751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. (2004). Identification of human brain tumour initiating cells. Nature 432: 396–401.

    Article  CAS  PubMed  Google Scholar 

  • Tan AR, Alexe G, Reiss M . (2009). Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Res Treat 115: 453–495.

    Article  CAS  PubMed  Google Scholar 

  • ten Dijke P . (2006). Bone morphogenetic protein signal transduction in bone. Curr Med Res Opin 22 (Suppl 1): S7–S11.

    Article  CAS  PubMed  Google Scholar 

  • Uchino M, Kojima H, Wada K, Imada M, Onoda F, Satofuka H et al. (2010). Nuclear beta-catenin and CD44 upregulation characterize invasive cell populations in non-aggressive MCF-7 breast cancer cells. BMC Cancer 10: 414.

    Article  PubMed  PubMed Central  Google Scholar 

  • Valera E, Isaacs MJ, Kawakami Y, Izpisua Belmonte JC, Choe S . (2010). BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells. PLoS One 5: e11167.

    Article  PubMed  PubMed Central  Google Scholar 

  • van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Lippitt JM, Guzman-Ramirez N et al. (2010). High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res 70: 5163–5173.

    Article  CAS  PubMed  Google Scholar 

  • van der Pluijm G, Que I, Sijmons B, Buijs JT, Lowik CW, Wetterwald A et al. (2005). Interference with the microenvironmental support impairs the de novo formation of bone metastases in vivo. Cancer Res 65: 7682–7690.

    Article  CAS  PubMed  Google Scholar 

  • van der Pluijm G . (2010). Epithelial plasticity, cancer stem cells and bone metastasis formation. Bone 48: 37–43.

    Article  PubMed  Google Scholar 

  • Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A et al. (2009). The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11: 1487–1495.

    Article  CAS  PubMed  Google Scholar 

  • Wicha MS, Liu S, Dontu G . (2006). Cancer stem cells: an old idea—a paradigm shift. Cancer Res 66: 1883–1890; discussion 1895–1886.

    Article  CAS  PubMed  Google Scholar 

  • Winquist RJ, Boucher DM, Wood M, Furey BF . (2009). Targeting cancer stem cells for more effective therapies: taking out cancer's locomotive engine. Biochem Pharmacol 78: 326–334.

    Article  CAS  PubMed  Google Scholar 

  • Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM . (2007). WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA 104: 618–623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao M, Zhao Z, Koh JT, Jin T, Franceschi RT . (2005). Combinatorial gene therapy for bone regeneration: cooperative interactions between adenovirus vectors expressing bone morphogenetic proteins 2, 4, and 7. J Cell Biochem 95: 1–16.

    Article  CAS  PubMed  Google Scholar 

  • Zhu W, Rawlins BA, Boachie-Adjei O, Myers ER, Arimizu J, Choi E et al. (2004). Combined bone morphogenetic protein-2 and -7 gene transfer enhances osteoblastic differentiation and spine fusion in a rodent model. J Bone Miner Res 19: 2021–2032.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Professor Dr P ten Dijke for providing the reporter constructs. JTB and GvdH were sponsored by the European Sixth Framework Programme PRIMA; CvdH and HC were sponsored by the European Sixth Framework Programme PROMET; MP was sponsored by the European Sixth Framework Programme BRECOSM and PGMvO was sponsored by a grant from Dutch Cancer Society (KWF project UL-2004-3028).

Author information

Authors and Affiliations

  1. Department of Urology, Leiden University Medical Center, Leiden, The Netherlands

    J T Buijs, G van der Horst, C van den Hoogen, H Cheung, B de Rooij, J Kroon, M Petersen, P G M van Overveld, R C M Pelger & G van der Pluijm

  2. Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

    G van der Pluijm

Authors
  1. J T Buijs
    View author publications

    Search author on:PubMed Google Scholar

  2. G van der Horst
    View author publications

    Search author on:PubMed Google Scholar

  3. C van den Hoogen
    View author publications

    Search author on:PubMed Google Scholar

  4. H Cheung
    View author publications

    Search author on:PubMed Google Scholar

  5. B de Rooij
    View author publications

    Search author on:PubMed Google Scholar

  6. J Kroon
    View author publications

    Search author on:PubMed Google Scholar

  7. M Petersen
    View author publications

    Search author on:PubMed Google Scholar

  8. P G M van Overveld
    View author publications

    Search author on:PubMed Google Scholar

  9. R C M Pelger
    View author publications

    Search author on:PubMed Google Scholar

  10. G van der Pluijm
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to G van der Pluijm.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buijs, J., van der Horst, G., van den Hoogen, C. et al. The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene 31, 2164–2174 (2012). https://doi.org/10.1038/onc.2011.400

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/onc.2011.400

Keywords

This article is cited by

Search

Advanced search

Quick links