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CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo

Cancer Gene Therapy volume 12, pages 84–89 (2005)Cite this article

Abstract

Breast cancer cells express the chemokine receptor CXCR4 and frequently metastasize to organs with an abundant source of the CXCR4 ligand, stromal cell-derived factor 1 (SDF-1). The chemokine receptor CXCR4 plays an active role in the metastasis of breast cancer. Here, we show that a small interfering RNA (siRNA) against CXCR4 effectively downregulates CXCR4 expression in human MDA-MB-231 breast cancer cells, leading to significant decrease in breast cancer cell invasion and adhesion. It was further found that tumor cells lacking CXCR4 expression proliferated at a much slower rate than control cells in vitro. Surprisingly, tumor cells lacking CXCR4 expression failed to grow in SCID mice in repeated experiments, providing the first direct evidence for an essential role of CXCR4 in breast cancer growth in vivo. This finding suggests an expanded role for the CXCR4 molecule in tumor cell growth in vivo, in addition to its role in breast cancer metastasis. This study implies the CXCR4 molecule as a potential target to control breast tumor growth as well as metastasis.

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References

  1. Moser B, Loetscher P . Lymphocyte traffic control by chemokines. Nat Immunol. 2001; 2: 123–128.

    Article  CAS  Google Scholar 

  2. Gupta SK, Lysko PG, Pillarisetti K, Ohlstein E, Stadel JM . Chemokine receptors in human endothelial cells. Functional expression of CXCR4 and its transcriptional regulation by inflammatory cytokines. J Biol Chem. 1998; 273: 4282–4287.

    Article  CAS  Google Scholar 

  3. Nakajima T, Tachibana K, Iizasa H, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Proc Nat Acad Sci USA. 1996; 93: 14726–14729.

    Article  Google Scholar 

  4. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001; 410: 50–56.

    Article  CAS  Google Scholar 

  5. Alenius H, Muller A, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nat Med. 2002; 8: 157–165.

    Article  Google Scholar 

  6. Bennett I, Cronholm P, Ochroch A, Taichman D, Taichman RS . Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. J Urol. 2002; 168: 203–204.

    Article  Google Scholar 

  7. Schrader AJ, Lechner O, Templin M, et al. CXCR4/CXCL12 expression and signalling in kidney cancer. Br J Cancer. 2002; 86: 1250–1256.

    Article  CAS  Google Scholar 

  8. Geminder H, Sagi-Assif O, Goldberg L, et al. A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J Immunol. 2001; 167: 4747–4757.

    Article  CAS  Google Scholar 

  9. Scotton CJ, Wilson JL, Scott K, et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Combination of quinupristin/dalfopristin and glycopeptide in severe methicillin-resistant staphylococcal infections failing previous glycopeptide regimens. Cancer Res. 2002; 62: 5930–5938.

    CAS  PubMed  Google Scholar 

  10. Murakami T, Maki W, Cardones AR, et al. Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res. 2002; 62: 7328–7334.

    CAS  PubMed  Google Scholar 

  11. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR . Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 1998; 393: 524–525.

    Article  Google Scholar 

  12. Tachibana K, Hirota S, Iizasa H, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature. 1998; 393: 591–594.

    Article  CAS  Google Scholar 

  13. Chen X, Beutler JA, McCloud TG, et al. Tannic acid is an inhibitor of CXCL12 (SDF-1alpha)/CXCR4 with antiangiogenic activity. Clin Cancer Res. 2003; 9: 3115–3123.

    CAS  PubMed  Google Scholar 

  14. Sun YX, Wang J, Shelburne CE, et al. Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. J Cell Biochem. 2003; 89: 462–473.

    Article  CAS  Google Scholar 

  15. Brummelkamp TR, Bernards R, Agami R . A system for stable expression of short interfering RNAs in mammalian cells. Science. 2002; 296: 550–553.

    Article  CAS  Google Scholar 

  16. Lapteva N, Ide K, Nieda M, et al. Activation and suppression of renin-angiotensin system in human dendritic cells. Biochem Biophys Res Commun. 2002; 296: 194–200.

    Article  CAS  Google Scholar 

  17. Wawersik M, Coulombe PA . Forced expression of keratin 16 alters the adhesion, differentiation, and migration of mouse skin keratinocytes. Mol Biol Cell. 2000; 11: 3315–3327.

    Article  CAS  Google Scholar 

  18. Strausberg RL, Feingold EA, Grouse LH, et al. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci USA. 2002; 99: 899–903.

    Google Scholar 

  19. Chen Y, Stamatoyannopoulos G, Song CZ . Down-regulation of CXCR4 by inducible small interfering RNA inhibits breast cancer cell invasion in vitro. Cancer Res. 2003; 63: 4801–4804.

    CAS  PubMed  Google Scholar 

  20. Libura J, Drukala J, Majka M, et al. CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood. 2002; 100: 2597–2606.

    Article  CAS  Google Scholar 

  21. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W . Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature. 2003; 425: 307–311.

    Article  CAS  Google Scholar 

  22. Barbero S, Bonavia R, Bajetto A, et al. Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res. 2003; 63: 1969–1974.

    CAS  PubMed  Google Scholar 

  23. Chen JD, Bai X, Yang AG, Cong Y, Chen SY . Inactivation of HIV-1 chemokine co-receptor CXCR-4 by a novel intrakine strategy. Nat Med. 1997; 3: 1110–1116.

    Article  CAS  Google Scholar 

  24. Schroers R, Davis CM, Wagner HJ, Chen SY . Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection. Gene Therapy. 2002; 9: 889–897.

    Article  CAS  Google Scholar 

  25. Zeelenberg IS, Ruuls-Van Stalle L, Roos E . The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases. Cancer Res. 2003; 63: 3833–3839.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Reuven Agami for providing us with the pSuper vector and Wenhong Ren, Lisa Rollins, Tatiana Goltsova for technical assistance.

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Author notes

  1. Natalia Lapteva, An-Gang Yang and Si-Yi Chen: These authors contributed equally to the study.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, 77030, USA

    Natalia Lapteva, An-Gang Yang, Denise E Sanders, Randall W Strube & Si-Yi Chen

  2. Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xian, China

    An-Gang Yang

Authors
  1. Natalia Lapteva
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  2. An-Gang Yang
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  3. Denise E Sanders
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  4. Randall W Strube
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  5. Si-Yi Chen
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Correspondence to Si-Yi Chen.

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Lapteva, N., Yang, AG., Sanders, D. et al. CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo. Cancer Gene Ther 12, 84–89 (2005). https://doi.org/10.1038/sj.cgt.7700770

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