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Breast Cancer Research and Treatment

, Volume 124, Issue 1, pp 89–99 | Cite as

The role of microRNA-128a in regulating TGFbeta signaling in letrozole-resistant breast cancer cells

  • Selma Masri
  • Zheng Liu
  • Sheryl Phung
  • Emily Wang
  • Yate-Ching Yuan
  • Shiuan Chen
Preclinical study

Abstract

Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of hormone refractory cell lines identified 115 differentially regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. A group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and selectively up-regulated in the letrozole-resistant cell lines. Human miR-128a was predicted to target the TGFβ signaling pathway and indeed sensitivity to TGFβ was compromised in the letrozole-resistant cells, as compared to parental MCF-7aro. Human miR-128a was shown to negatively target TGFβRI protein expression by binding to the 3′UTR region of the gene. Inhibition of endogenous miR-128a resulted in resensitization of the letrozole-resistant lines to TGFβ growth inhibitory effects. These data suggest that the hormone-responsive miR-128a can modulate TGFβ signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFβ signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance.

Keywords

Aromatase inhibitor resistance MicroRNA MiR-128a TGFβ Estrogen 

Notes

Acknowledgments

The authors would like to thank Dr. Xiwei Wu and Dr. Min (Sierra) Li for help with microarray processing and statistical analysis.

Support: NIH pre-doctoral training fellowship CA123691 to S. Masri and NIH grant CA044735 to S. Chen.

Supplementary material

10549_2009_716_MOESM1_ESM.tif (2.1 mb)
Supplementary material 1 (TIFF 2105 kb)

References

  1. 1.
    Yager JD, Liehr JG (1996) Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol 36:203–232CrossRefPubMedGoogle Scholar
  2. 2.
    Yue W, Santen RJ, Wang JP et al (2003) Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. J Steroid Biochem Mol Biol 86(3–5):477–486CrossRefPubMedGoogle Scholar
  3. 3.
    Santner SJ, Chen S, Zhou D, Korsunsky Z, Martel J, Santen RJ (1993) Effect of androstenedione on growth of untransfected and aromatase-transfected MCF-7 cells in culture. J Steroid Biochem Mol Biol 44(4–6):611–616CrossRefPubMedGoogle Scholar
  4. 4.
    Yue W, Wang JP, Hamilton CJ, Demers LM, Santen RJ (1998) In situ aromatization enhances breast tumor estradiol levels and cellular proliferation. Cancer Res 58(5):927–932PubMedGoogle Scholar
  5. 5.
    Early Breast Cancer Trialists’ Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351(9114):1451–1467Google Scholar
  6. 6.
    Coombes RC, Hall E, Gibson LJ et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350(11):1081–1092CrossRefPubMedGoogle Scholar
  7. 7.
    Goss PE, Ingle JN, Martino S et al (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349(19):1793–1802CrossRefPubMedGoogle Scholar
  8. 8.
    Howell A, Cuzick J, Baum M et al (2005) Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365(9453):60–62CrossRefPubMedGoogle Scholar
  9. 9.
    Britton DJ, Hutcheson IR, Knowlden JM et al (2006) Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat 96(2):131–146CrossRefPubMedGoogle Scholar
  10. 10.
    Massarweh S, Osborne CK, Creighton CJ et al (2008) Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 68(3):826–833CrossRefPubMedGoogle Scholar
  11. 11.
    Jelovac D, Sabnis G, Long BJ, Macedo L, Goloubeva OG, Brodie AM (2005) Activation of mitogen-activated protein kinase in xenografts and cells during prolonged treatment with aromatase inhibitor letrozole. Cancer Res 65(12):5380–5389CrossRefPubMedGoogle Scholar
  12. 12.
    Santen RJ, Song RX, Zhang Z, Yue W, Kumar R (2004) Adaptive hypersensitivity to estrogen: mechanism for sequential responses to hormonal therapy in breast cancer. Clin Cancer Res 10(1 Pt 2):337S–345SCrossRefPubMedGoogle Scholar
  13. 13.
    Masri S, Phung S, Wang X et al (2008) Genome-wide analysis of aromatase inhibitor-resistant, tamoxifen-resistant, and long-term estrogen-deprived cells reveals a role for estrogen receptor. Cancer Res 68(12):4910–4918CrossRefPubMedGoogle Scholar
  14. 14.
    Chan CM, Martin LA, Johnston SR, Ali S, Dowsett M (2002) Molecular changes associated with the acquisition of oestrogen hypersensitivity in MCF-7 breast cancer cells on long-term oestrogen deprivation. J Steroid Biochem Mol Biol 81(4–5):333–341CrossRefPubMedGoogle Scholar
  15. 15.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297CrossRefPubMedGoogle Scholar
  16. 16.
    Llave C, Xie Z, Kasschau KD, Carrington JC (2002) Cleavage of scarecrow-like mRNA targets directed by a class of Arabidopsis miRNA. Science 297(5589):2053–2056CrossRefPubMedGoogle Scholar
  17. 17.
    Palatnik JF, Allen E, Wu X et al (2003) Control of leaf morphogenesis by microRNAs. Nature 425(6955):257–263CrossRefPubMedGoogle Scholar
  18. 18.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854CrossRefPubMedGoogle Scholar
  19. 19.
    Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75(5):855–862CrossRefPubMedGoogle Scholar
  20. 20.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6(4):259–269CrossRefPubMedGoogle Scholar
  21. 21.
    Cimmino A, Calin GA, Fabbri M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102(39):13944–13949CrossRefPubMedGoogle Scholar
  22. 22.
    Johnson SM, Grosshans H, Shingara J et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120(5):635–647CrossRefPubMedGoogle Scholar
  23. 23.
    O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435(7043):839–843CrossRefPubMedGoogle Scholar
  24. 24.
    Huang Q, Gumireddy K, Schrier M et al (2008) The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol 10(2):202–210CrossRefPubMedGoogle Scholar
  25. 25.
    Ma L, Teruya-Feldstein J, Weinberg RA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449(7163):682–688CrossRefPubMedGoogle Scholar
  26. 26.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massague J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370(6488):341–347CrossRefPubMedGoogle Scholar
  27. 27.
    Feng XH, Derynck R (2005) Specificity and versatility in tgf-beta signaling through Smads. Annu Rev cell Dev Biol 21:659–693CrossRefPubMedGoogle Scholar
  28. 28.
    Buck MB, Knabbe C (2006) TGF-beta signaling in breast cancer. Ann NY Acad Sci 1089:119–126CrossRefPubMedGoogle Scholar
  29. 29.
    Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J (2003) Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci USA 100(14):8430–8435CrossRefPubMedGoogle Scholar
  30. 30.
    Muraoka RS, Koh Y, Roebuck LR et al (2003) Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1. Mol Cell Biol 23(23):8691–8703CrossRefPubMedGoogle Scholar
  31. 31.
    Tucker RF, Shipley GD, Moses HL, Holley RW (1984) Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science 226(4675):705–707CrossRefPubMedGoogle Scholar
  32. 32.
    Kalkhoven E, Beraldi E, Panno ML, De Winter JP, Thijssen JH, Van Der Burg B (1996) Growth inhibition by anti-estrogens and progestins in TGF-beta-resistant and -sensitive breast-tumor cells. Int J Cancer 65(5):682–687CrossRefPubMedGoogle Scholar
  33. 33.
    Arteaga CL, Koli KM, Dugger TC, Clarke R (1999) Reversal of tamoxifen resistance of human breast carcinomas in vivo by neutralizing antibodies to transforming growth factor-beta. J Natl Cancer Inst 91(1):46–53CrossRefPubMedGoogle Scholar
  34. 34.
    Yoo YA, Kim YH, Kim JS, Seo JH (2008) The functional implications of Akt activity and TGF-beta signaling in tamoxifen-resistant breast cancer. Biochim Biophys Acta 1783(3):438–447CrossRefPubMedGoogle Scholar
  35. 35.
    Sun XZ, Zhou D, Chen S (1997) Autocrine and paracrine actions of breast tumor aromatase. A three-dimensional cell culture study involving aromatase transfected MCF-7 and T-47D cells. J Steroid Biochem Mol Biol 63(1–3):29–36CrossRefPubMedGoogle Scholar
  36. 36.
    Lonning PE (2009) Lack of complete cross-resistance between different aromatase inhibitors; a real finding in search for an explanation? Eur J Cancer 45(4):527–535CrossRefPubMedGoogle Scholar
  37. 37.
    Chen S, Masri S, Hong Y et al (2007) New experimental models for aromatase inhibitor resistance. J Steroid Biochem Mol Biol 106(1–5):8–15CrossRefPubMedGoogle Scholar
  38. 38.
    Miller TE, Ghoshal K, Ramaswamy B et al (2008) MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem 283(44):29897–29903CrossRefPubMedGoogle Scholar
  39. 39.
    Zhao JJ, Lin J, Yang H et al (2008) MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem 283(45):31079–31086CrossRefPubMedGoogle Scholar
  40. 40.
    Foekens JA, Sieuwerts AM, Smid M et al (2008) Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer. Proc Natl Acad Sci USA 105(35):13021–13026CrossRefPubMedGoogle Scholar
  41. 41.
    Blenkiron C, Goldstein LD, Thorne NP et al (2007) MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol 8(10):R214CrossRefPubMedGoogle Scholar
  42. 42.
    Castellano L, Giamas G, Jacob J et al (2009) The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci USA 106(37):15732–15737CrossRefPubMedGoogle Scholar
  43. 43.
    Creighton CJ, Nagaraja AK, Hanash SM, Matzuk MM, Gunaratne PH (2008) A bioinformatics tool for linking gene expression profiling results with public databases of microRNA target predictions. RNA (New York, NY) 14(11):2290–2296Google Scholar
  44. 44.
    Bhat-Nakshatri P, Wang G, Collins NR et al (2009) Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Res 37(14):4850–4861CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Selma Masri
    • 1
  • Zheng Liu
    • 2
  • Sheryl Phung
    • 1
  • Emily Wang
    • 1
  • Yate-Ching Yuan
    • 2
  • Shiuan Chen
    • 1
  1. 1.Division of Tumor Cell BiologyBeckman Research Institute of the City of HopeDuarteUSA
  2. 2.Division of Information SciencesBeckman Research Institute of the City of HopeDuarteUSA

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