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Heregulin-β1 regulates the estrogen receptor-α gene expression and activity via the ErbB2/PI 3-K/Akt pathway

Oncogene volume 22, pages 2073–2087 (2003)Cite this article

A Retraction to this article was published on 10 March 2005

Abstract

This study examines whether the serine/threonine protein kinase, Akt, is involved in the crosstalk between the ErbB2 and estrogen receptor-α (ER-α) pathways. Treatment of MCF-7 cells with 10−9 M heregulin-β1 (HRG-β1) resulted in a rapid phosphorylation of Akt and a 15-fold increase in Akt activity. Akt phosphorylation was blocked by inhibitors of phosphatidylinositol 3-kinase (PI 3-K), by antiestrogens, the protein tyrosine kinase inhibitor, genistein, and by AG825, a selective ErbB2 inhibitor; but not by AG30, a selective EGFR inhibitor. Akt phosphorylation by HRG-β1 was abrogated by an arginine to cysteine mutation (R25C) in the pleckstrin homology (PH) domain of Akt, and HRG-β1 did not induce Akt phosphorylation in the ER-negative variant of MCF-7, MCF-7/ADR. Transient transfection of ER-α into these cells restored Akt phosphorylation by HRG-β1, suggesting the requirement of ER-α. HRG-β1 did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. Stable transfection of the cells with a dominant negative Akt or with the R25C-Akt mutant, as well as PI 3-K inhibitors, blocked the effect of HRG-β1 on ER-α expression and activity and on the growth of MCF-7 cells. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of HRG-β1. Experiments employing selective ErbB inhibitors demonstrate that the effect of HRG-β1 on ER-α expression and activity is also mediated by ErbB2 and not by EGFR, demonstrating that ErbB2 is the primary mediator of the effects of HRG-β1 on ER-α regulation. Taken together, our data suggest that HRG-β1, bound to the ErbB2 ErbB3 heterodimer, in the presence of membrane ER-α, interacts with and activates PI 3-K/Akt. Akt leads to nuclear ER-α phosphorylation, thereby altering its expression and transcriptional activity.

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References

  • Aguilar Z, Akita RW, Finn RS, Ramos BL, Pegram MD, Kabbinavar FF, Pietras RJ, Pisacane P, Sliwkowski MX and Slamon DJ . (1999). Oncogene, 18, 6050–6062.

  • Ahmed NN, Franke TF, Bellacosa A, Datta K, Gonzalez-Portal ME, Taguchi T, Testa JR and Tsichlis PN . (1993). Oncogene, 8, 1957–1963.

  • Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P and Hemmings BA . (1996). EMBO J., 15, 6541–6551.

  • Allred DC, Clark GM, Molina R, Tandon AK, Schnitt SJ, Gilchrist KW, Osborne CK, Tormey DC and McGuire WL . (1992). Hum. Pathol., 23, 974–979.

  • Andjelkovic M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM and Hemmings BA . (1997). J. Biol. Chem., Dec 12; 272, 31515–31524.

  • Angus WG, Campaigne Larsen M and Jefcoate CR . (2000). Mol. Cell Endocrinol., 170, 1–13.

  • Antoniotti S, Maggiora P, Dati C and De Bortoli M . (1992). Eur. J. Cancer, 28, 318–321.

  • Bates NP and Hurst HC . (1997). Oncogene, 15, 473–481.

  • Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V, Ferrandina G, Panici PB, Mancuso S, Neri G and Testa JR . (1995). Int. J. Cancer, 64, 280–285.

  • Benchaibi M, Mallet F, Thoraval P, Savatier P, Xiao JH, Verdier G, Samarut J and Nigon V . (1989). Virology, 169, 15–26.

  • Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, Shepard HM and Osborne CK . (1993). Breast Cancer Res. Treat., 24, 85–95.

  • Berns EM, Foekens JA, van Putten WL, van Staveren IL, Portengen H, de Koning WC and Klijn JG . (1992). J. Steroid Biochem. Mol. Biol., 43, 13–19.

  • Berry M, Metzger D and Chambon P . (1990). EMBO J., 9, 2811–2818.

  • Berthois Y, Pourreau-Schneider N, Gandilhon P, Mittre H, Tubiana N and Martin PM . (1986). J. Steroid Biochem., 25, 963–972.

  • Brockhoff G, Heiss P, Schlegel J, Hofstaedter F and Knuechel R . (2001). Cytometry, 44, 338–348.

  • Burgering BM and Coffer PJ . (1995). Nature, 376, 599–602.

  • Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S and Nakshatri H . (2001). J. Biol. Chem., 276, 9817–9824.

  • Carraway III KL and Cantley LC . (1994). Cell, 78, 5–8.

  • Carraway III KL, Soltoff SP, Diamonti AJ and Cantley LC . (1995). J. Biol. Chem., 270, 7111–7116.

  • Chen X, Yeung TK and Wang Z . (2000). Biochem. Biophys. Res. Commun., 277, 757–763.

  • Cheng JQ, Altomare DA, Klein MA, Lee WC, Kruh GD, Lissy NA and Testa JR . (1997). Oncogene, 14, 2793–2801.

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

  • Chung YL, Sheu ML, Yang SC, Lin CH and Yen SH . (2002). Int. J. Cancer, 97, 306–312.

  • Daly RJ . (1999). Growth Factors, 16, 255–263.

  • Dauvois S, White R and Parker MG . (1993). J. Cell Sci., 106 (Part 4), 1377–1388.

  • De Potter CR, Beghin C, Makar AP, Vandekerckhove D and Roels HJ . (1990). Int. J. Cancer, 45, 55–58.

  • Dougall WC, Qian X, Peterson NC, Miller MJ, Samanta A and Greene MI . (1994). Oncogene, 9, 2109–2123.

  • Downward J . (1995). Nature, 376, 553–554.

  • El-Tanani MK and Green CD . (1997a). Mol. Endocrinol., 11, 928–937.

  • El-Tanani MK and Green CD . (1997b). J. Steroid Biochem. Mol. Biol., 60, 269–276.

  • Falls DL, Rosen KM, Corfas G, Lane WS and Fischbach GD . (1993). Cell, 72, 801–815.

  • Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR and Tsichlis PN . (1995). Cell, 81, 727–736.

  • Garcia-Morales P, Saceda M, Kenney N, Kim N, Salomon DS, Gottardis MM, Solomon HB, Sholler PF, Jordan VC and Martin MB . (1994). J. Biol. Chem., 269, 16896–16901.

  • Grunt TW, Saceda M, Martin MB, Lupu R, Dittrich E, Krupitza G, Harant H, Huber H and Dittrich C . (1995). Int. J. Cancer, 63, 560–567.

  • Gullick WJ . (1990). Prog. Growth Factor Res., 2, 1–13.

  • Gullick WJ . (1991). Hum. Exp. Toxicol., 10, 398–400.

  • Gusterson BA, Gelber RD, Goldhirsch A, Price KN, Save-Soderborgh J, Anbazhagan R, Styles J, Rudenstam CM, Golouh R and Reed R et al. (1992). J. Clin. Oncol., 10, 1049–1056.

  • Harris JR, Lippman ME, Veronesi U and Willett W . (1992). N. Engl. J. Med., 327, 473–480.

  • Hemmings BA . (1997). Science, 277, 534.

  • Hoda K, Sawada H, Kihara T, Urushitani M, Nakamizo T, Akaike A and Shimohama S . (2000). J. Neurosci. Res., 60, 321–327.

  • Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD et al. (1992). Science, 256, 1205–1210.

  • Houston SJ, Plunkett TA, Barnes DM, Smith P, Rubens RD and Miles DW . (1999). Br. J. Cancer, 79, 1220–1226.

  • Hynes NE and Stern DF . (1994). Biochim. Biophys. Acta, 1198, 165–184.

  • Ignar-Trowbridge DM, Nelson KG, Bidwell MC, Curtis SW, Washburn TF, McLachlan JA and Korach KS . (1992). Proc. Natl. Acad. Sci. USA, 89, 4658–4662.

  • Ignar-Trowbridge DM, Teng CT, Ross KA, Parker MG, Korach KS and McLachlan JA . (1993). Mol. Endocrinol., 7, 992–998.

  • Improta-Brears T, Whorton AR, Codazzi F, York JD, Meyer T and McDonnell DP (1999). Proc. Natl. Acad. Sci. USA, 96, 4686–4691.

  • Juhl H, Downing SG and Wellstein A . (1997). J. Biol. Chem., 272, 29482–29486.

  • Kato S . (2001). Breast Cancer, 8, 3–9.

  • Keshamouni VG, Mattingly RR and Reddy KB . (2002) J. Biol. Chem., 277, 22558–22565.

  • Kim HH, Sierke SL and Koland JG (1994). J. Biol. Chem., 269, 24747–24755.

  • Kim HP, Lee JY, Jeong JK, Bae SW, Lee HK and Jo I . (1999). Biochem. Biophys. Res. Commun., 263, 257–262.

  • King CR, Borrello I, Bellot F, Comoglio P and Schlessinger J . (1988). EMBO J., 7, 1647–1651.

  • Klippel A, Reinhard C, Kavanaugh WM, Apell G, Escobedo MA and Williams LT . (1996). Mol. Cell. Biol., 16, 4117–4127.

  • Konishi H, Kuroda S, Tanaka M, Matsuzaki H, Ono Y, Kameyama K, Haga T and Kikkawa U . (1995). Biochem. Biophys. Res. Commun., 216, 526–534.

  • Kraus MH, Issing W, Miki T, Popescu NC and Aaronson SA . (1989). Proc. Natl. Acad. Sci. USA, 86, 9193–9197.

  • Kurokawa H, Lenferink AE, Simpson JF, Pisacane PL, Sliwkowski MX, Forbes JT and Arteaga CL . (2000). Cancer Res., 60, 5887–5894.

  • Lichtner RB, Parczyk K, Birchmeier W and Schneider MR . (1999). J. Steroid Biochem. Mol. Biol., 71, 181–189.

  • Liu W, Li J and Roth RA . (1999). Biochem. Biophys. Res. Commun., 261, 897–903.

  • Liu Y, el-Ashry D, Chen D, Ding IY and Kern FG . (1995). Breast Cancer Res. Treat., 34, 97–117.

  • Lupu R, Cardillo M, Cho C, Harris L, Hijazi M, Perez C, Rosenberg K, Yang D and Tang C . (1996). Breast Cancer Res. Treat., 38, 57–66.

  • Lupu R and Lippman ME . (1993). Breast Cancer Res. Treat., 27, 83–93.

  • Lupu R, Wellstein A, Sheridan J, Ennis BW, Zugmaier G, Katz D, Lippman ME and Dickson RB . (1992). Biochemistry, 31, 7330–7340.

  • Marquez DC and Pietras RJ . (2001). Oncogene, 20, 5420–5430.

  • Martin MB, Franke TF, Stoica GE, Chambon P, Katzenellenbogen BS, Stoica BA, McLemore MS, Olivo SE and Stoica A . (2000). Endocrinology, 141, 4503–4511.

  • Matsuda S, Kadowaki Y, Ichino M, Akiyama T, Toyoshima K and Yamamoto T . (1993). Proc. Natl. Acad. Sci. USA, 90, 10803–10807.

  • McLeskey SW, Kurebayashi J, Honig SF, Zwiebel J, Lippman ME, Dickson RB and Kern FG . (1993). Cancer Res., 53, 2168–2177.

  • Menard S, Tagliabue E, Campiglio M and Balsari A . (2000). J. Natl. Cancer Inst., 92, 943–944.

  • Mermelstein PG, Becker JB and Surmeier DJ . (1996). J. Neurosci., 16, 595–604.

  • Metzger D, Berry M, Ali S and Chambon P . (1995). Mol. Endocrinol., 9, 579–591.

  • Mimnaugh EG, Fairchild CR, Fruehauf JP and Sinha BK . (1991). Biochem. Pharmacol., 42, 391–402.

  • Miwa W, Yasuda J, Murakami Y, Yashima K, Sugano K, Sekine T, Kono A, Egawa S, Yamaguchi K, Hayashizaki Y and Sekiya T . (1996). Biochem. Biophys. Res. Commun., 225, 968–974.

  • Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ and Roth RA . (1999). J. Biol. Chem., 274, 21528–21532.

  • Nicholson RI, McClelland RA, Finlay P, Eaton CL, Gullick WJ, Dixon AR, Robertson JF, Ellis IO and Blamey RW . (1993). Eur. J. Cancer, 29A, 1018–1023.

  • Normanno N, Kim N, Wen D, Smith K, Harris AL, Plowman G, Colletta G, Ciardiello F and Salomon DS . (1995). Breast Cancer Res. Treat., 35, 293–297.

  • Orti E, Bodwell JE and Munck A . (1992). Endocrinol. Rev., 13, 105–128.

  • Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, Schlessinger J, Lippman ME and King CR . (1990). J. Clin. Oncol., 8, 103–112.

  • Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, Levy RB and Yarden Y . (1992). Cell, 69, 205–216.

  • Pierce JH, Arnstein P, DiMarco E, Artrip J, Kraus MH, Lonardo F, Di Fiore PP and Aaronson SA . (1991). Oncogene, 6, 1189–1194.

  • Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, Ramos L, Gorman CM, Parker MG, Sliwkowski MX and Slamon DJ . (1995). Oncogene, 10, 2435–2446.

  • Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG and Shoyab M . (1993). Proc. Natl. Acad. Sci. USA, 90, 1746–1750.

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

  • Puricelli L, Proiettii CJ, Labriola L, Salatino M, Balana ME, Ghiso JA, Lupu R, Pignataro OP, Charreau EH, Bal de Kier Joffe E and Elizalde PV . (2002). Int. J. Cancer, 100, 642–653.

  • Quenel N, Wafflart J, Bonichon F, de Mascarel I, Trojani M, Durand M, Avril A and Coindre JM . (1995). Breast Cancer Res. Treat., 35, 283–291.

  • Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, Cohen L, Mohr RN, Bazan JF, Howard M, Copeland NG Jenkins NA and Witte ON . (1993). Science, 261, 358–361.

  • Razandi M, Pedram A, Greene GL and Levin ER . (1999). Mol. Endocrinol., 13, 307–319.

  • Read LD, Greene GL and Katzenellenbogen BS . (1989). Mol. Endocrinol., 3, 295–304.

  • Read LD, Keith Jr D, Slamon DJ and Katzenellenbogen BS . (1990). Cancer Res., 50, 3947–3951.

  • Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossman R, Reid K, Moelling K, Yancopoulos GD and Glass DJ . (1999). Science, 286, 1738–1741.

  • Russell KS and Hung MC . (1992). Cancer Res., 52, 6624–6629.

  • Saceda M, Grunt TW, Colomer R, Lippman ME, Lupu R and Martin MB . (1996). Endocrinology, 137, 4322–4330.

  • Saceda M, Lippman ME, Chambon P, Lindsey RL, Ponglikitmongol M, Puente M and Martin MB . (1988). Mol. Endocrinol., 2, 1157–1162.

  • Sepp-Lorenzino L, Eberhard L, Ma Z, Cho S, Serve H, Liu F, Rosen N and Lupu R . (1996). Oncogene, 12, 1679–1687.

  • Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW and Liao JK . (2000). Nature, 407, 538–541.

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, 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.

  • Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A, Fendly BM, Cerione RA, Vandlen RL and Carraway III KL . (1994). J. Biol. Chem., 269, 14661–14665.

  • Soltoff SP, Carraway 3rd KL, Prigent SA, Gullick WJ and Cantley LC . (1994). Mol. Cell. Biol., 14, 3550–3558.

  • Stevis PE, Deecher DC, Suhadolnik L, Mallis LM and Frail DE . (1999) Endocrinology, 140, 5455–5458.

  • Stoica A, Saceda M, Doraiswamy VL, Coleman C and Martin MB . (2000a). J. Endocrinol., 165, 371–378.

  • Stoica A, Saceda M, Fakhro A, Joyner M and Martin MB . (2000b). J. Cell. Biochem., 76, 605–614.

  • Stoica A, Saceda M, Fakhro A, Solomon HB, Fenster BD and Martin MB . (1997). Endocrinology, 138, 1498–1505.

  • Stoica GE, Franke TF, Moroni M, Muller M, Wellstein A, Morgan E, Martin MB and Stoica A . (2003a). The effect of estradiol on ER-a gene expression and activity can be modulated by Akt, Oncogene (submitted).

  • Stoica GE, Franke TF, Wellstein A, Czubayko F., List HJ, Reiter R, Martin MB, Morgan E and Stoica A . (2003b). Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Mol. Endocrinol. (in press).

  • Sweeney C, Fambrough D, Huard C, Diamonti AJ, Lander ES, Cantley LC and Carraway III KL . (2001). J. Biol. Chem., 276, 22685–22698.

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

  • Tang CK, Perez C, Grunt T, Waibel C, Cho C and Lupu R . (1996). Cancer Res., 56, 3350–3358.

  • Tauchi K, Hori S, Itoh H, Osamura RY, Tokuda Y and Tajima T . (1989). Virchows Arch. A. Pathol. Anat. Histopathol., 416, 65–73.

  • Taverna D, Antoniotti S, Maggiora P, Dati C, De Bortoli M and Hynes NE . (1994). Int. J. Cancer, 56, 522–528.

  • Tsutsui S, Ohno S, Murakami S, Hachitanda Y and Oda S . (2002). J. Surg. Oncol., 79, 216–223.

  • Tzahar E and Yarden Y . (1998). Biochim. Biophys. Acta., 1377, M25–M37.

  • Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger J et al. (1984). Nature, 309, 418–425.

  • Watters JJ, Campbell JS, Cunningham MJ, Krebs EG and Dorsa DM . (1997). Endocrinology, 138, 4030–4033.

  • Weigel NL . (1996). Biochem. J., 319 (Part 3), 657–667.

  • Wosikowski K, Schuurhuis D, Kops GJ, Saceda M and Bates SE . (1997). Clin. Cancer Res., 3, 2405–2414.

  • Wright C, Cairns J, Cantwell BJ, Cattan AR, Hall AG, Harris AL and Horne CH . (1992). Br. J. Cancer, 65, 271–274.

  • Yamamoto T, Akiyama T, Yokota J, Mori S and Toyoshima K . (1986). Princess Takamatsu Symp., 17, 203–210.

  • Yoo JY, Lessor T and Hamburger AW . (1998). Breast Cancer Res. Treat., 51, 71–81.

  • Zhou BP, Hu MC, Miller SA, Yu Z, Xia W, Lin SY and Hung MC . (2000) J. Biol. Chem., 275, 8027–8031.

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Acknowledgements

We thank Dr P Chambon for the ER-α expression vector and Drs C Tang and D Gamett for critical reading of the manuscript. This work was supported by grants from the Milheim Foundation and Georgetown University (Dean of Research) (to AS) and, in part, by CDA DAMD17-00-1-0214 to (TFF). Support for tissue culture and cell cycle analysis core facilities was provided by P50-CA-58185 and P30-CA-51008.

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  1. Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, 20007, DC, USA

    Gerald E Stoica, Anton Wellstein, Heinz-Joachim List, Ronald Reiter, Mary Beth Martin & Adriana Stoica

  2. Department of Pharmacology, Columbia University, 10032, NY, USA

    Thomas F Franke

  3. School of Nursing and Health Studies, Georgetown University, Washington, 20007, DC, USA

    Elisha Morgan & Adriana Stoica

  4. Department of Pharmacology and Toxicology, School of Medicine, Philipps University, Karl-von-Frisch Strasse 1, Marburg, 35033, Germany

    Frank Czubayko

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Stoica, G., Franke, T., Wellstein, A. et al. Heregulin-β1 regulates the estrogen receptor-α gene expression and activity via the ErbB2/PI 3-K/Akt pathway. Oncogene 22, 2073–2087 (2003). https://doi.org/10.1038/sj.onc.1206311

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