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Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

Oncogene volume 25, pages 3286–3295 (2006)Cite this article

Abstract

Although ErbB2 is known to enhance breast cancer metastasis, the signaling events responsible for this remain elusive. α-Isozyme of protein kinase C (PKCα), which is involved in cancer development and progression, has been suggested to be activated by ErbB2 without direct evidence. In addition, the roles of PKCα in ErbB2-mediated cancer cell malignancy have not been clearly identified. In this study, we investigated whether ErbB2 can activate PKCα and determined what role PKCα plays in ErbB2-mediated breast cancer cell invasion. We expressed wild-type and mutant ErbB2 with altered signaling capacities in MDA-MB-435 breast cancer cells and revealed that overexpression or activation of ErbB2 in MDA-MB-435 cells upregulated and activated PKCα and that downregulation of ErbB2 by small-interfering RNA decreased the expression and activity of PKCα in BT474 breast cancer cells. These in vitro results were supported by data from breast cancer patient samples. In 150 breast cancer tumor samples, ErbB2-overexpressing tumors showed significantly higher positive rates of PKCα membrane immunohistochemistry staining than that of ErbB2-low-expressing tumors. Mechanistically, we found that PKCα is co-immunoprecipitated with Src and PKCα expression and activity can be decreased by Src inhibitor PP2 and by the expression of a dominant-negative mutant of Src. Moreover, ErbB2-mediated upregulation of urokinase-type plasminogen activator receptor (uPAR) is reduced by either the PKCα inhibitor Go6976 or the Src inhibitor PP2, and the combination of Go6976 with PP2 is superior to either agent alone in suppressing uPAR expression and cell invasion. These results demonstrate that PKCα is critical for ErbB2-mediated cancer cell invasion and provide valuable insights for current and future PKCα and Src inhibitor clinical trials.

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References

  • Bornancin F, Parker PJ . (1996). Curr Biol 6: 1114–1123.

  • Boyd DD, Wang H, Avila H, Parikh NU, Kessler H, Magdolen V et al. (2004). Clin Cancer Res 10: 1545–1555.

  • de Bono JS, Tolcher AW, Rowinsky EK . (2003). Breast Cancer Res 5: 154–159.

  • Dempsey EC, Newton AC, Mochly-Rosen D, Fields AP, Reyland ME, Insel PA et al. (2000). Am J Physiol Lung Cell Mol Physiol 279: L429–L438.

  • Gum R, Wang SW, Lengyel E, Yu D, Hung MC, Juarez J et al. (1995). Anticancer Res 15: 1167–1172.

  • Holbro T, Civenni G, Hynes NE . (2003). Exp Cell Res 284: 99–110.

  • Holbro T, Hynes NE . (2004). Annu Rev Pharmacol Toxicol 44: 195–217.

  • Huigsloot M, Tijdens RB, van de Water B . (2003). Mol Pharmacol 64: 965–973.

  • Ishizawar R, Parsons SJ . (2004). Cancer Cell 6: 209–214.

  • Johnson MD, Torri JA, Lippman ME, Dickson RB . (1999). Exp Cell Res 247: 105–113.

  • Klos KS, Zhou X, Lee S, Zhang L, Yang W, Nagata Y et al. (2003). Cancer 98: 1377–1385.

  • Lahn M, Kohler G, Sundell K, Su C, Li S, Paterson BM et al. (2004). Oncology 67: 1–10.

  • Longo M, Brama M, Marino M, Bernardini S, Korach KS, Wetsel WC et al. (2004). Bone 34: 100–111.

  • Martin GS . (2001). Nat Rev Mol Cell Biol 2: 467–475.

  • Masur K, Lang K, Niggemann B, Zanker KS, Entschladen F . (2001). Mol Biol Cell 12: 1973–1982.

  • Michie AM, Nakagawa R . (2005). Immunol Lett 96: 155–162.

  • Moody SE, Sarkisian CJ, Hahn KT, Gunther EJ, Pickup S, Dugan KD et al. (2002). Cancer Cell 2: 451–461.

  • Morse-Gaudio M, Connolly JM, Rose DP . (1998). Int J Oncol 12: 1349–1354.

  • Muthuswamy SK, Muller WJ . (1995). Oncogene 11: 1801–1810.

  • Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA et al. (2004). Cancer Cell 6: 117–127.

  • Nishizuka Y . (1992). Science 258: 607–614.

  • Palka HL, Green KJ . (1997). J Cell Sci 110 (Part 19): 2359–2371.

  • Parekh DB, Ziegler W, Parker PJ . (2000). EMBO J 19: 496–503.

  • Parker PJ, Murray-Rust J . (2004). J Cell Sci 117: 131–132.

  • Peles E, Levy RB, Or E, Ullrich A, Yarden Y . (1991). EMBO J 10: 2077–2086.

  • Sidenius N, Blasi F . (2003). Cancer Metastasis Rev 22: 205–222.

  • Sliva D . (2004). Curr Cancer Drug Targets 4: 327–336.

  • Summy JM, Gallick GE . (2003). Cancer Metastasis Rev 22: 337–358.

  • Tan M, Grijalva R, Yu D . (1999). Cancer Res 59: 1620–1625.

  • Tan M, Li P, Klos KS, Lu J, Lan KH, Nagata Y et al. (2005). Cancer Res 65: 1858–1867.

  • Tan M, Yao J, Yu D . (1997). Cancer Res 57: 1199–1205.

  • Van der Geer P, Hunter T, Lindberg RA . (1994). Ann Rev Cell Biol 10: 251–337.

  • Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al. (1988). N Engl J Med 319: 525–532.

  • Ways DK, Kukoly CA, deVente J, Hooker JL, Bryant WO, Posekany KJ et al. (1995). J Clin Invest 95: 1906–1915.

  • Yarden Y, Sliwkowski MX . (2001). Nat Rev Mol Cell Biol 2: 127–137.

  • Yeatman TJ . (2004). Nat Rev Cancer 4: 470–480.

  • Yu D, Jing T, Liu B, Yao J, Tan M, McDonnell TJ et al. (1998). Mol Cell 2: 581–591.

  • Yu D, Liu B, Tan M, Li J, Wang SS, Hung MC . (1996). Oncogene 13: 1359–1365.

  • Zhou X, Tan M, Stone Hawthorne V, Klos KS, Lan KH, Yang Y et al. (2004). Clin Cancer Res 10: 6779–6788.

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Acknowledgements

The pSV2 expression vectors of the ErbB2 mutants were provided by Dr Tadashi Yamamoto of Tokyo University, and the Src mutant expression vectors were provided by Dr David Shalloway of Cornell University. The PKCα mutant expression vectors were provided by Dr Gottfried Baier of the University of Innsbruck. We thank Kristine Broglio for statistical analysis; Nolan Smith for technical assistance; Martha Morrison and Gayle Nesom for editing the manuscript. This work was supported by NIH Grants P30-CA16672 (MDACC), 2RO1-CA60488, 1RO1-CA109570, RO1-CA112567, PO1-CA099031 project 4 (DY) and an MDACC institutional research grant (MT).

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  1. Departments of Surgical Oncology, Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Tan, P Li, M Sun & D Yu

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Yin

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Correspondence to D Yu.

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Tan, M., Li, P., Sun, M. et al. Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors. Oncogene 25, 3286–3295 (2006). https://doi.org/10.1038/sj.onc.1209361

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