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Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016

Abstract

The expression of the NH2 terminally truncated ErbB2 receptor (p95ErbB2) in breast cancer correlates with metastatic disease progression compared with the expression of full-length p185ErbB2. We now show that heregulin (HRG), but not EGF, stimulates p95ErbB2 phosphorylation in BT474 breast cancer cells. Furthermore, phospho-p95ErbB2 forms heterodimers with ErbB3, but not EGFR, while p185ErbB2 heterodimerizes with both EGFR and ErbB3. The predilection of p95ErbB2 to heterodimerize with ErbB3 provides an explanation for its regulation by HRG, an ErbB3 ligand. GW572016, a reversible small molecule inhibitor of EGFR and ErbB2 tyrosine kinases, inhibits baseline p95ErbB2 phosphorylation in BT474 cells and tumor xenografts. Inhibition of p95ErbB2, p185ErbB2, and EGFR phosphorylation by GW572016 resulted in the inhibition of downstream phospho-Erk1/2, phospho-AKT, and cyclin D steady-state protein levels. Increased phosphorylation of p95ErbB2 and AKT in response to HRG was abrogated to varying degrees by GW572016. In contrast, trastuzumab did not inhibit p95ErbB2 phosphorylation or the expression of downstream phospho-Erk1/2, phospho-AKT, or cyclin D. It is tempting to speculate that trastuzumab resistance may be mediated in part by the selection of p95ErbB2-expressing breast cancer cells capable of exerting potent growth and prosurvival signals through p95ErbB2-ErbB3 heterodimers. Thus, p95ErbB2 represents a target for therapeutic intervention, and one that is sensitive to GW572016 therapy.

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References

  • Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, Di Fiore PP and Kraus MH . (1995). Oncogene, 10, 1813–1821.

  • Bacus SS, Altomare DA, Lyass L, Chin DM, Farrell MP, Gurova K, Gudkov A and Testa JR . (2002). Oncogene, 21, 3532–3540.

  • Bacus SS, Zelnick CR, Plowman G and Yarden Y . (1994). Am. J. Clin. Pathol., 102, S13–S24.

  • Bargmann CI and Weinberg RA . (1988). EMBO J., 7, 2043–2052.

  • Beerli RR, Graus-Porta D, Woods-Cook K, Chen X, Yarden Y and Hynes NE . (1995). Mol. Cell. Biol., 15, 6496–6505.

  • Brandt-Rauf PW . (1995). Mutat. Res., 333, 203–208.

  • Cheng J, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, Tsichlis PN and Testa JR . (1992). Proc. Natl. Acad. Sci. USA, 89, 9267–9271.

  • Christianson TA, Doherty JK, Lin YJ, Ramsey EE, Holmes R, Keenan EJ and Clinton GM . (1998). Cancer Res., 58, 5123–5129.

  • Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter J, Paton V, Shak S, Lieberman G and Slamon DJ . (1999). J. Clin. Oncol., 17, 2639–2648.

  • Cockerill S, Stubberfield C, Stables J, Carter M, Guntrip S, Smith K, McKeown S, Shaw R, Topley P, Thomsen L, Affleck K, Jowett A, Hayes D, Willson M, Woollard P and Spalding D . (2001). Bioorg. Med. Chem. Lett., 11, 1401–1405.

  • Codony J, Albanell J, Lopez-Talavera JC, Arribas J and Baselga J . (1999). Cancer Res., 59, 1196–1201.

  • Colomer R, Montero S, Lluch A, Ojeda B, Barnadas A, Casado A, Massuti A, Cortes-Funes J and Lloveras B . (2000). Clin. Cancer Res., 6, 2356–2362.

  • Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR and Aaronson SA . (1987). Science, 237, 178–182.

  • Graus-Porta D, Beerli RR, Daly JM and Hynes NE . (1997). EMBO J., 16, 1647–1655.

  • Gullick WJ, Love SB, Wright C, Barnes DM, Gusterson B, Harris AJ and Altman DG . (1991). Br. J. Cancer, 63, 434–438.

  • Hackel PO, Zwick E, Prenzel N and Ullrich A . (1999). Curr. Opin. Cell Biol., 11, 184–189.

  • Harris RA, Eichholtz TJ, Hiles JD, Page MT and O'Hare MJ . (1999). Int. J. Cancer, 80, 477–484.

  • Kandl H, Seymour L and Bezwoda WR . (1994). Br. J. Cancer, 70, 739–742.

  • Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, Seger R, Hynes NE and Yarden Y . (1996). EMBO J., 15, 254–264.

  • Klapper LN, Kirschbaum MH, Sela M and Yarden Y . (2000). Adv. Cancer Res., 77, 25–79.

  • Lemoine NR, Barnes DM, Hollywood DP, Hughes CM, Smith P, Dublin E, Prigent SA, Gullick WJ and Hurst HC . (1992). Br. J. Cancer, 66, 1116–1121.

  • Levkowitz G, Klapper LN, Tzahar E, Freywald A, Sela M and Yarden Y . (1996). Oncogene, 12, 1117–1125.

  • Lin YJ and Clinton GM . (1991). Oncogene, 6, 639–643.

  • Luttrell DK, Lee TJ, Lansing TJ, Crosby RM, Jung KD, Willard D, Luther M, Rodriguez J, Berman J and Gilmer TM . (1994). Proc. Natl. Acad. Sci. USA, 91, 83–87.

  • Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J and Baselga J . (2001). Cancer Res., 61, 4744–4749.

  • Molina MA, Saez R, Ramsey EE, Garcia-Barchino M-J, Rojo F, Evans AJ, Albanell J, Keenan EJ, Lluch A, Garcia-Conde J, Baselga J and Clinton GM . (2002). Clin. Cancer Res., 8, 347–353.

  • Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B and Hynes NE . (1998). Mol. Cell. Biol., 18, 5042–5051.

  • Prigent SA and Gullick WJ . (1994). EMBO J., 13, 2831–2841.

  • Pupa SM, Crepaldi L, Gandino S, Longati P and Comoglio P . (1993). Oncogene, 8, 2917–2923.

  • Rajikumar T and Gullick WJ . (1994). Breast Cancer Res. Treat., 29, 3–9.

  • Reise DJ and Stern DF . (1998). Bioessays, 20, 41–48.

  • Rusnak DW, Lackey K, Affleck K, Wood ER, Alligood KJ, Rhodes N, Keith BR, Murray DM, Glennon K, Knight WB, Mullin RJ and Gilmer TM . (2001). Mol. Cancer Ther., 1, 85–94.

  • Salomon DD, Brandt R, Ciardiello F and Normanno N . (1995). Crit. Rev. Oncol. Hematol., 19, 183–232.

  • Segatto O, King CR, Pierce JH, DiFiore PP and Aaronson SA . (1988). Mol. Cell. Biol., 8, 5570–5574.

  • Sibilia M and Wagner EF . (1995). Science, 269, 234–238.

  • Siegel PM, Ryan ED, Cardiff RD and Muller WJ . (1999). EMBO J., 18, 2149–2164.

  • Slamon DJ, Clark SG, Wong WJ, Levin A, Ullrich A and McGuire WL . (1987). Science, 235, 177–182.

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A and Press MF . (1989). Science, 244, 707–712.

  • Soltoff SP, Carraway III KL, Prigent SA, Gullick WJ and Cantley LC . (1994). Mol. Cell. Biol., 14, 3550–3558.

  • Stamenkovic I . (2000). Semin. Cancer Biol., 10, 415–433.

  • Stern DF and Kamps MP . (1988). EMBO J., 7, 995–1001.

  • Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, Lamantia C, Mourton T, Herrup K, Harris RC, Barnard JA, Yuspa SH, Coffey RJ and Magnuson T . (1995). Science, 269, 230–234.

  • Tsai MS, Shamon-Taylor LA, Mehmi I, Tang CK and Lupu R . (2003). Oncogene, 22, 761–768.

  • Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ and Yarden Y . (1996). Mol. Cell. Biol., 16, 5276–5287.

  • Ullrich A and Schlessinger J . (1990). Cell, 61, 203–212.

  • Vivanco I and Sawyers CL . (2002). Nat Rev/Cancer, 2, 489–501.

  • Wada T, Qian XL and Greene MI . (1990). Cell, 61, 1339–1347.

  • Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS and Vogelstein B . (1992). Proc. Natl. Acad. Sci. USA, 89, 2965–2969.

  • Xia W, Mullin RJ, Keith BR, Liu L-H, Ma H, Rusnak DW, Owens G, Alligood KJ and Spector NL . (2002). Oncogene, 21, 6255–6263.

  • Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S and Arteaga CL . (2002). Cancer Res., 62, 4132–4141.

  • Yamauchi H, O'Neill A, Gelman R, Carney W, Tenney DY, Hosch S and Hayes DF . (1997). J. Clin. Oncol., 15, 2518–2525.

  • Zabrecky JR, Lam T, McKenzie SJ and Carney W . (1991). J. Biol. Chem., 266, 1716–1720.

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Acknowledgements

We thank Barry Keith, Robert Mullin, and James Onori for providing assistance with tumor xenografts. We also thank Arthur Moseley, Wanda Bodnar, Mary Moyer, Bob Hollingsworth, and Roderick Davis for their assistance in helping to identify p95 as well as Tona Gilmer and Allen Oliff for helpful discussions.

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Correspondence to Neil L Spector.

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Xia, W., Liu, LH., Ho, P. et al. Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 23, 646–653 (2004). https://doi.org/10.1038/sj.onc.1207166

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