Breast Cancer Research and Treatment

, Volume 137, Issue 2, pp 373–382 | Cite as

MicroRNA-30c targets cytoskeleton genes involved in breast cancer cell invasion

  • Jessica Bockhorn
  • Kathy Yee
  • Ya-Fang Chang
  • Aleix Prat
  • Dezheng Huo
  • Chika Nwachukwu
  • Rachel Dalton
  • Simo Huang
  • Kaitlin E. Swanson
  • Charles M. Perou
  • Olufunmilayo I. Olopade
  • Michael F. Clarke
  • Geoffrey L. Greene
  • Huiping Liu
Preclinical study

Abstract

Metastasis remains a significant challenge in treating cancer. A better understanding of the molecular mechanisms underlying metastasis is needed to develop more effective treatments. Here, we show that human breast tumor biomarker miR-30c regulates invasion by targeting the cytoskeleton network genes encoding twinfilin 1 (TWF1) and vimentin (VIM). Both VIM and TWF1 have been shown to regulate epithelial-to-mesenchymal transition. Similar to TWF1, VIM also regulates F-actin formation, a key component of cellular transition to a more invasive mesenchymal phenotype. To further characterize the role of the TWF1 pathway in breast cancer, we found that IL-11 is an important target of TWF1 that regulates breast cancer cell invasion and STAT3 phosphorylation. The miR-30c-VIM/TWF1 signaling cascade is also associated with clinical outcome in breast cancer patients.

Keywords

miR-30c Breast tumor invasion TWF1 VIM IL-11 

Supplementary material

10549_2012_2346_MOESM1_ESM.pdf (374 kb)
Supplementary material 1 (PDF 374 kb)

References

  1. 1.
    Sporn MB (1996) The war on cancer. Lancet 347(9012):1377–1381PubMedCrossRefGoogle Scholar
  2. 2.
    Prat A, Perou CM (2011) Deconstructing the molecular portraits of breast cancer. Mol Oncol 5(1):5–23. doi:10.1016/j.molonc.2010.11.003 PubMedCrossRefGoogle Scholar
  3. 3.
    Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12(5):R68. doi:10.1186/bcr2635 PubMedCrossRefGoogle Scholar
  4. 4.
    Prat A, Perou CM (2009) Mammary development meets cancer genomics. Nat Med 15(8):842–844. doi:10.1038/nm0809-842 PubMedCrossRefGoogle Scholar
  5. 5.
    Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15(8):907–913. doi:10.1038/nm.2000 PubMedCrossRefGoogle Scholar
  6. 6.
    Bockhorn J, Dalton R, Nwachukwu C, Huang S, Prat A, Yee K, Chang Y-F, Huo D, Wen Y, Swanson KE, Qiu T, Lu J, Park SY, Dolan ME, Perou CM, Olopade OI, Clarke MF, Greene GL, Liu H (2012) MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nature Commun (in press)Google Scholar
  7. 7.
    Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14(6):818–829. doi:10.1016/j.devcel.2008.05.009 PubMedCrossRefGoogle Scholar
  8. 8.
    Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29(34):4741–4751. doi:10.1016/j.devcel.2008.05.009 PubMedCrossRefGoogle Scholar
  9. 9.
    Meacham CE, Ho EE, Dubrovsky E, Gertler FB, Hemann MT (2009) In vivo RNAi screening identifies regulators of actin dynamics as key determinants of lymphoma progression. Nat Genet 41(10):1133–1137PubMedCrossRefGoogle Scholar
  10. 10.
    Liu H, Patel MR, Prescher JA, Patsialou A, Qian D, Lin J, Wen S, Chang YF, Bachmann MH, Shimono Y, Dalerba P, Adorno M, Lobo N, Bueno J, Dirbas FM, Goswami S, Somlo G, Condeelis J, Contag CH, Gambhir SS, Clarke MF (2010) Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci U S A 107(42):18115–18120PubMedCrossRefGoogle Scholar
  11. 11.
    Team RDC (2011) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, AustriaGoogle Scholar
  12. 12.
    Buffa FM, Camps C, Winchester L, Snell CE, Gee HE, Sheldon H, Taylor M, Harris AL, Ragoussis J (2011) microRNA-associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer. Cancer Res 71(17):5635–5645PubMedCrossRefGoogle Scholar
  13. 13.
    Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65(16):7065–7070. doi:10.1158/0008-5472.CAN-05-1783 PubMedCrossRefGoogle Scholar
  14. 14.
    Liu H (2012) MicroRNAs in breast cancer initiation and progression. Cell Mol Life Sci. doi:10.1007/s00018-012-1128-9 Google Scholar
  15. 15.
    Antonov AV, Dietmann S, Wong P, Lutter D, Mewes HW (2009) GeneSet2miRNA: finding the signature of cooperative miRNA activities in the gene lists. Nucleic Acids Res 37 (Web Server issue):W323-328. doi: 10.1093/nar/gkp313
  16. 16.
    Palmgren S, Vartiainen M, Lappalainen P (2002) Twinfilin, a molecular mailman for actin monomers. J Cell Sci 115(Pt 5):881–886PubMedGoogle Scholar
  17. 17.
    Ojala PJ, Paavilainen VO, Vartiainen MK, Tuma R, Weeds AG, Lappalainen P (2002) The two ADF-H domains of twinfilin play functionally distinct roles in interactions with actin monomers. Mol Biol Cell 13(11):3811–3821. doi:10.1091/mbc.E02-03-0157 PubMedCrossRefGoogle Scholar
  18. 18.
    Poukkula M, Kremneva E, Serlachius M, Lappalainen P (2011) Actin-depolymerizing factor homology domain: a conserved fold performing diverse roles in cytoskeletal dynamics. Cytoskeleton (Hoboken) 68(9):471–490. doi:10.1002/cm.20530 Google Scholar
  19. 19.
    Ernst M, Najdovska M, Grail D, Lundgren-May T, Buchert M, Tye H, Matthews VB, Armes J, Bhathal PS, Hughes NR, Marcusson EG, Karras JG, Na S, Sedgwick JD, Hertzog PJ, Jenkins BJ (2008) STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest 118(5):1727–1738. doi:10.1172/JCI34944 PubMedGoogle Scholar
  20. 20.
    Schuringa JJ, Wierenga AT, Kruijer W, Vellenga E (2000) Constitutive Stat3, Tyr705, and Ser727 phosphorylation in acute myeloid leukemia cells caused by the autocrine secretion of interleukin-6. Blood 95(12):3765–3770PubMedGoogle Scholar
  21. 21.
    Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of microRNA-target recognition. PLoS Biol 3(3):e85. doi:10.1371/journal.pbio.0030085 PubMedCrossRefGoogle Scholar
  22. 22.
    Li N, Kaur S, Greshock J, Lassus H, Zhong X, Wang Y, Leminen A, Shao Z, Hu X, Liang S, Katsaros D, Huang Q, Butzow R, Weber BL, Coukos G, Zhang L (2012) A combined array-based comparative genomic hybridization and functional library screening approach identifies mir-30d as an oncomir in cancer. Cancer Res 72(1):154–164. doi:10.1158/0008-5472.CAN-11-2484 PubMedCrossRefGoogle Scholar
  23. 23.
    Gaziel-Sovran A, Segura MF, Di Micco R, Collins MK, Hanniford D, de Vega-Saenz Miera E, Rakus JF, Dankert JF, Shang S, Kerbel RS, Bhardwaj N, Shao Y, Darvishian F, Zavadil J, Erlebacher A, Mahal LK, Osman I, Hernando E (2011) miR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Cancer Cell 20(1):104–118. doi:10.1016/j.ccr.2011.05.027 PubMedCrossRefGoogle Scholar
  24. 24.
    Elson-Schwab I, Lorentzen A, Marshall CJ (2010) MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion. PloS one 5 (10). doi:10.1371/journal.pone.0013176
  25. 25.
    Cheng CW, Wang HW, Chang CW, Chu HW, Chen CY, Yu JC, Chao JI, Liu HF, Ding SL, Shen CY (2012) MicroRNA-30a inhibits cell migration and invasion by downregulating vimentin expression and is a potential prognostic marker in breast cancer. Breast Cancer Res Treat 134(3):1081–1093. doi:10.1007/s10549-012-2034-4 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Jessica Bockhorn
    • 1
    • 2
  • Kathy Yee
    • 1
  • Ya-Fang Chang
    • 1
  • Aleix Prat
    • 3
    • 7
  • Dezheng Huo
    • 4
  • Chika Nwachukwu
    • 5
  • Rachel Dalton
    • 1
  • Simo Huang
    • 1
  • Kaitlin E. Swanson
    • 1
  • Charles M. Perou
    • 3
  • Olufunmilayo I. Olopade
    • 5
  • Michael F. Clarke
    • 6
  • Geoffrey L. Greene
    • 1
  • Huiping Liu
    • 1
    • 6
  1. 1.The Ben May Department for Cancer ResearchThe University of ChicagoChicagoUSA
  2. 2.Department of Biochemistry and Molecular BiologyThe University of ChicagoChicagoUSA
  3. 3.Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillUSA
  4. 4.Department of Health StudiesThe University of ChicagoChicagoUSA
  5. 5.Center for Clinical Cancer Genetics, Department of MedicineThe University of ChicagoChicagoUSA
  6. 6.The Institute for Stem Cell Biology and Regenerative MedicineStanford UniversityStanfordUSA
  7. 7.Translational Genomics GroupVall D′Hebron Institute of Oncology (VHIO)BarcelonaSpain

Personalised recommendations