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Signaling events mediated by α3β1 integrin are essential for mammary tumorigenesis

Oncogene volume 33, pages 4286–4295 (2014)Cite this article

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Abstract

The constitutive activation of β-catenin signaling in the mammary basal epithelial cell layer in transgenic K5ΔNβcat mice leads to basal-type tumor development. Integrins of the β1 family and integrin-mediated signaling events have an important role in breast tumor growth and progression. We show here that the deletion of α3β1 integrin, a major laminin receptor, from the basal layer of the mammary epithelium of K5ΔNβcat mice completely prevented the tumorigenesis induced by β-catenin signaling. Moreover, the depletion of α3β1 integrin from a spontaneously transformed mouse mammary basal epithelial cell line (MEC) prevented the cells from forming colonies in soft agar and greatly reduced tumor development in orthotopic grafts. Inhibition of the integrin signaling intermediates Rac1 or PAK1 (P21-activated Kinase 1) in MEC affected tumor cell growth in soft agar, whereas the expression of activated forms of these effectors in α3-depleted cells rescued the capacity of these cells to grow in non-adherent conditions. Similarly, the tumorigenic potential of α3-depleted cells was restored by the expression of activated PAK1, as assessed by orthotopic transplantation assay. In three-dimensional Matrigel culture, MEC survival and proliferation were affected by the depletion of α3β1 integrin, which also significantly decreased the activation of focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK). Our data suggest that the activation of signaling cascades downstream from α3β1 and involving the Rac1/PAK1 pathway, MAPK and JNK, promotes prosurvival and proproliferative signals required for the malignant growth of basal mammary epithelial cells, providing further insight into the molecular mechanisms underlying breast cancer initiation and progression.

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References

  1. Prat A, Ellis MJ, Perou CM . Practical implications of gene-expression-based assays for breast oncologists. Nat Rev Clin Oncol 2011; 9: 48–57.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001; 98: 10869–10874.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Reis-Filho JS, Pusztai L . Gene expression profiling in breast cancer: classification, prognostication, and prediction. Lancet 2011; 378: 1812–1823.

    Article  CAS  PubMed  Google Scholar 

  4. Bertucci F, Finetti P, Birnbaum D . Basal breast cancer: a complex and deadly molecular subtype. Curr Mol Med 2012; 12: 96–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF et alCancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61–70.

    Article  CAS  Google Scholar 

  6. DiMeo TA, Anderson K, Phadke P, Cheng F, Perou CM, Naber S et al. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res 2009; 69: 5364–5373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI, Goss KH . Wnt/β-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol 2010; 76: 2911–2920.

    Article  Google Scholar 

  8. Hynes RO . Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110: 673–687.

    Article  CAS  PubMed  Google Scholar 

  9. Huveneers S, Danen EHJ . Adhesion signaling-crosstalk between integrins, Src and Rho. J Cell Sci 2009; 122: 1059–1069.

    Article  CAS  PubMed  Google Scholar 

  10. Raymond K, Faraldo MM, Deugnier MA, Glukhova MA . Integrins in mammary development. Semin Cell Dev Biol 2012; 23: 599–605.

    Article  CAS  PubMed  Google Scholar 

  11. Streuli CH, Akhtar N . Signal co-operation between integrins and other receptor systems. Biochem J 2009; 418: 491–506.

    Article  CAS  PubMed  Google Scholar 

  12. Cabodi S, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P . Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer 2010; 10: 858–870.

    Article  CAS  PubMed  Google Scholar 

  13. Rathinam R, Alahari SK . Important role of integrins in the cancer biology. Cancer Metast Rev 2010; 29: 223–237.

    Article  CAS  Google Scholar 

  14. Lahlou H, Muller WJ . β1-Integrins, signaling and mammary tumor progression in transgenic mouse models: implications for human breast cancer. Breast Cancer Res 2011; 13: 229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jonjic N, Lucin K, Krstulja M, Iternicka Z, Mustac E . Expression of beta-1 integrins on tumor cells of invasive ductal breast carcinoma. Pathol Res Pract 1993; 189: 979–984.

    Article  CAS  PubMed  Google Scholar 

  16. Yao ES, Zhang H, Chen YY, Lee B, Chew K, Moore D et al. Increased β1 integrin is associated with decreased survival in invasive breast cancer. Cancer Res 2007; 67: 659–664.

    Article  CAS  PubMed  Google Scholar 

  17. Morini M, Mottolese M, Ferrari N, Ghiorzo F, Buglioni S, Mortarini R et al. The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. Int J Cancer 2000; 87: 336–342.

    Article  CAS  PubMed  Google Scholar 

  18. Cance WG, Harris JE, Iacocca MV, Roche E, Yang X, Chang J et al. 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; 6: 2417–2423.

    CAS  PubMed  Google Scholar 

  19. Luo M, Guan JL . Focal adhesion kinase: a prominent determinant in breast cancer initiation, progression and metastasis. Cancer Lett 2010; 289: 127–139.

    Article  CAS  PubMed  Google Scholar 

  20. Lambert AW, Ozturk S, Thiagalingam S . Integrin signaling in mammary epithelial cells and breast cancer. ISRN Oncol 2012; 2012: 493283.

    PubMed  PubMed Central  Google Scholar 

  21. Pylayeva Y, Gillen KM, Gerald W, Beggs HE, Reichardt LF, Giancotti FG . Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Invest 2009; 119: 252–266.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Bianchi-Smiraglia A, Paesante S, Bakin AV . Integrin β5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways. Oncogene 2013; 32: 3049–3058.

    Article  CAS  PubMed  Google Scholar 

  23. Taddei I, Faraldo MM, Teulière J, Deugnier MA, Thiery JP, Glukhova MA . Integrins in mammary gland development and differentiation of mammary epithelium. J Mam Gland Biol Neopl 2003; 8: 383–394.

    Article  Google Scholar 

  24. Raymond K, Cagnet S, Kreft M, Janssen H, Sonnneberg A, Glukhova MA . Control of mammary myoepithelial cell contractile function by α3β1 integrin signalling. EMBO J 2011; 30: 1896–1906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mitchell K, Svenson KB, Longmate WM, Gkirtzimanaki K, Sadej R, Wang X et al. Suppression of integrin alpha3beta1 in breast cancer cells reduces cyclooxygenase-2 gene expression and inhibits tumorigenesis, invasion, and cross-talk to endothelial cells. Cancer Res 2010; 70: 6359–6367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Novitskaya V, Romanska H, Dawoud M, Jones JL, Berditchevski F . Tetraspanin CD151 regulates growth of mammary epithelial cells in three-dimensional extracellular matrix: implication for mammary ductal carcinoma in situ. Cancer Res 2010; 70: 4698–4708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Subbaram S, Dipersio CM . Integrin α3β1 as a breast cancer target. Expert Opin Ther Targets 2011; 15: 1197–1210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Teulière J, Faraldo MM, Deugnier MA, Shtutman M, Ben-Ze'ev A, Thiery JP et al. Targeted activation of beta-catenin signaling in basal mammary epithelial cells affects mammary development and leads to hyperplasia. Development 2005; 132: 267–277.

    Article  PubMed  Google Scholar 

  29. Moumen M, Chiche A, Decraene C, Petit V, Gandarillas A, Deugnier MA et al. Myc is required for beta-catenin-mediated mammary stem cell amplification and tumorigenesis. Mol Cancer (in revision).

  30. Peltonen J, Larjava H, Jaakkola S, Gralnick H, Akiyama SK, Yamada SS et al. Localization of integrin receptors for fibronectin, collagen, and laminin in human skin. Variable expression in basal and squamous cell carcinomas. J Clin Invest 1989; 84: 1916–1923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Elben ST, Slack JK, Weber MJ, Calting AD . Rac-PAK signaling stimulates extracellular signal-regulated kinase (ERK) activation by regulating formation of MEK1–ERK complexes. Mol Cell Biol 2002; 22: 6023–6033.

    Article  Google Scholar 

  32. Oktay M, Wary KK, Dans M, Birge RB, Giancotti FG . Integrin-mediated activation of focal adhesion is required for signaling to Jun NH2-terminal kinase and progression through the G1 phase of the cell cycle. J Cell Biol 1999; 145: 1461–1469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Roskoski R Jr . ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res 2012; 66: 105–143.

    Article  CAS  PubMed  Google Scholar 

  34. Choma DP, Pumiglia K, DiPersio CM . Integrin a3b1 directs the stabilization of a polarized lamellipodium in epithelial cells through activation of Rac1. J Cell Sci 2004; 117: 3947–3959.

    Article  CAS  PubMed  Google Scholar 

  35. Choma DP, Vincenzo M, Pumiglia KM, DiPersio CM . Integrin a3b1-dependent activation of FAK/Src regulates Rac1-mediated keratinocyte polarization on laminin-5. J Inv Dermatol 2007; 127: 31–40.

    Article  CAS  Google Scholar 

  36. Manohar A, Shome SG, Lamar J, Stirling L, Iyer V, Pumiglia K et al. Alpha 3 beta 1 integrin promotes keratinocyte cell survival through activation of a MEK/ERK signaling pathway. J Cell Sci 2004; 117: 4043–4054.

    Article  CAS  PubMed  Google Scholar 

  37. Bafico A, Liu G, Goldin L, Harris V, Aaronson SA . An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 2004; 6: 497–506.

    Article  CAS  PubMed  Google Scholar 

  38. Sachs N, Secades P, van Hulst L, Kreft M, Song JY, Sonnenberg A . Loss of integrin α3 prevents skin tumor formation by promoting epidermal turnover and depletion of slow-cycling cells. Proc Natl Acad Sci USA 2012; 109: 21468–21473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zeng YA, Nusse R . Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell 2011; 6: 568–577.

    Article  Google Scholar 

  40. Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/ β-catenin signaling. PLoS Biol 2009; 7: e1000121.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Taddei I, Deugnier MA, Faraldo MM, Petit V, Bouvard D, Medina D et al. Beta1 integrin deletion from the basal compartment of the mammary epithelium affects stem cells. Nat Cell Biol 2008; 10: 716–722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 2009; 15: 907–913.

    Article  CAS  PubMed  Google Scholar 

  43. Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 2010; 7: 403–417.

    Article  CAS  PubMed  Google Scholar 

  44. Ramirez A, Page A, Gandarillas A, Zanet J, Pibre S, Vidal M et al. A keratin K5Cre transgenic line appropriate for tissue- specific or generalized Cre-mediated recombination. Genesis 2004; 39: 52–57.

    Article  CAS  PubMed  Google Scholar 

  45. Margadant C, Raymond K, Kreft M, Sachs N, Janssen H, Sonnenberg A . Integrin α3β1 inhibits directional migration and wound re-epithelialization in the skin. J Cell Sci 2009; 122: 278–288.

    Article  CAS  PubMed  Google Scholar 

  46. Raymond K, Kreft M, Janssen H, Calafat J, Sonnenberg A . Keratinocytes display normal proliferation, survival and differentiation in conditional beta4-integrin knockout mice. J Cell Sci 2005; 118: 1045–1060.

    Article  CAS  PubMed  Google Scholar 

  47. Sachs N, Kreft M, van den Bergh Weerman MA, Beynon AJ, Peters TA, Weening JJ et al. Kidney failure in mice lacking the tetraspanin CD151. J Cell Biol 2006; 175: 33–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Moumen M, Chiche A, Deugnier MA, Petit V, Gandarillas A, Glukhova MA et al. The proto-oncogene Myc is essential for mammary stem cell function. Stem cells 2012; 30: 1246–1254.

    Article  CAS  PubMed  Google Scholar 

  49. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW et al. Constitutive transcriptional activation by a beta-catenin–Tcf complex in APC−/− colon carcinoma. Science 1997; 275: 1784–1787.

    Article  CAS  PubMed  Google Scholar 

  50. Salomon D, Sacco PA, Roy SG, Simcha I, Johnson KR, Wheelock MJ et al. Regulation of beta-catenin levels and localization by overexpression of plakoglobin and inhibition of the ubiquitin proteasome system. J Cell Biol 1997; 139: 1325–1335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are particularly grateful to Dr JL Jorcano for providing K5Cre transgenic mice. We thank Dr I Grandjean and S Jannet for excellent assistance with animal care, Z Maciorowski, A Viguier and S Grondin for excellent assistance with FACS analyses and M Denoyelle and A Di Cicco for technical help. We also thank the Nikon Imaging Centre at Institut Curie-CNRS for providing confocal microscopy facilities. This work was supported by La Ligue Nationale Contre le Cancer (Equipe Labélisée 2009, 2013) and a grant from the Agence Nationale de la Recherche ANR-08-BLAN-0078-01 to MAG. SC received funding from Association pour la Recherche sur le Cancer; MAG is Directeur de Recherche and MMF and KR are Chargé de Recherche at the Institut National de la Santé et de la Recherche Médicale (INSERM).

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Author notes

  1. K Raymond and M A Glukhova: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut Curie, Centre de Recherche, Paris, France

    S Cagnet, M M Faraldo, K Raymond & M A Glukhova

  2. Section de Recherche, UMR144 Centre National de la Recherche Scientifique-Institut Curie, Paris, France

    S Cagnet, M M Faraldo, K Raymond & M A Glukhova

  3. Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    M Kreft & A Sonnenberg

Authors
  1. S Cagnet
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  2. M M Faraldo
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Correspondence to K Raymond or M A Glukhova.

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Cagnet, S., Faraldo, M., Kreft, M. et al. Signaling events mediated by α3β1 integrin are essential for mammary tumorigenesis. Oncogene 33, 4286–4295 (2014). https://doi.org/10.1038/onc.2013.391

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Keywords

  • integrin signaling
  • basal-like breast cancer
  • mouse models of breast cancer
  • Wnt/β-catenin pathway
  • survival
  • proliferation

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