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Effect of estradiol on estrogen receptor-α gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway

Oncogene volume 22, pages 7998–8011 (2003)Cite this article

Abstract

Epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and heregulin-β1 (HRG-β1), can modulate the expression and activity of the estrogen receptor-α (ER-α) via the phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway in the ER-α-positive breast cancer cell line, MCF-7. Estradiol can also rapidly activate PI 3-K/Akt in these cells (nongenomic effect). The recent study examines whether Akt is involved in the ER-α regulation by estradiol (genomic effect). Stable transfection of parental MCF-7 cells with a dominant-negative Akt mutant, as well as the PI 3-K inhibitors wortmannin and LY 294,002, blocked the effect of estradiol on ER-α expression and activity by 70–80 and 55–63%, respectively. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of estradiol. The changes in ER-α expression and activity were abrogated in response to estradiol by an arginine to cysteine mutation in the pleckstrin homology (PH) domain of Akt (R25C), suggesting the involvement of this amino acid in the interaction between Akt and ER-α. Experiments employing selective ErbB inhibitors demonstrate that the effect of estradiol on ER-α expression and activity is mediated by ErbB2 and not by EGFR. Moreover, anchorage-dependent and -independent growth assays, cell cycle and membrane ruffling analyses showed that Akt exerts estrogen-like activity on cell growth and membrane ruffling and that a selective ErbB2 inhibitor, but not anti-ErbB2 antibodies directed to the extracellular domain, can block these effects. In the presence of constitutively active Akt, tamoxifen only partially inhibits cell growth. In contrast, in cells stably transfected with either a dominant-negative Akt or with R25C-Akt, as well as in parental cells in the presence of a selective ErbB2 inhibitor, the effect of estradiol on anchorage-dependent and -independent cell growth was inhibited by 50–75 and 100%, respectively. Dominant-negative Akt inhibited membrane ruffling by 54%; however, R25C-Akt did not have any effect, suggesting that kinase activity plays an important role in this process. Scatchard analysis demonstrated a 67% reduction in estrogen-binding capacity in cells transfected with constitutively active Akt. No change in binding affinity of estradiol to the receptor was observed upon transfection with either Akt mutant. Taken together, our results suggest that estradiol treatment results in binding to membrane ER-α and interaction with a heterodimer containing ErbB2, leading to tyrosine phosphorylation. This results in the activation of PI 3-K and Akt. Akt, in turn, may interact with nuclear ER-α, altering its expression and activity.

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References

  • 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.

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

  • Alroy I and Yarden Y . (1997). FEBS Lett., 410, 83–86 (review).

  • Andjelkovic M, Jakubowicz T, Cron P, Ming XF, Han JW and Hemmings BA . (1996). Proc. Natl. Acad. Sci. USA, 93, 5699–5704.

  • Arteaga CL, Coronado E and Osborne CK . (1988). Mol. Endocrinol., 2, 1064–1069.

  • Auricchio F, Di Domenico M, Migliaccio A, Castoria G and Bilancio A . (1995). Cell Growth Differ., 6, 105–113.

  • Bacus SS, Chin D, Yarden Y, Zelnick CR and Stern DF . (1996). Am. J. Pathol., 148, 549–558.

  • Beato M, Herrlich P and Schutz G . (1995). Cell, 83, 851–857 (review).

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

  • Berthois Y, Katzenellenbogen JA and Katzenellenbogen BS . (1986). Proc. Natl. Acad. Sci. USA, 83, 2496–2500.

  • Borg A, Baldetorp B, Ferno M, Killander D, Olsson H, Ryden S and Sigurdsson H . (1994). Cancer Lett., 81, 137–144.

  • 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 (review).

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

  • Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone MV and Auricchio F . (2001). EMBO J., 20, 6050–6059.

  • Craft N, Shostak Y, Carey M and Sawyers CL . (1999). Nat. Med., 5, 280–285.

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

  • Davis RJ . (1993). J. Biol. Chem., 268, 14553–14556 (review).

  • Dickson RB and Lippman ME . (1987). Endocr. Rev., 8, 29–43 (review).

  • Dickson RB and Lippman ME . (1995). Endocr. Rev., 16, 559–589 (review).

  • 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.

  • Guiochon-Mantel A, Delabre K, Lescop P and Milgrom E . (1996). J. Steroid Biochem. Mol. Biol., 56 (1–6 Spec No), 3–9 (review).

  • Heath JP and Holifield BF . (1991). Cell Motil. Cytoskel., 18, 245–257 (review).

  • Hellyer NJ, Kim MS and Koland JG . (2001). J. Biol. Chem., 276, 42153–42161.

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

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

  • Johnston SR . (1997). Anticancer Drugs, 8, 911–930 (review).

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

  • Kato S, Kitamoto T, Masuhiro Y and Yanagisawa J . (1998). Oncology, 55 (Suppl. 1), 5–10 (review).

  • Katzenellenbogen BS, Montano MM, Ekena K, Herman ME and McInerney EM . (1997). Breast Cancer Res. Treat., 44, 23–38 (review).

  • Kelly MJ and Levin ER . (2001). Trends Endocrinol. Metab., 12, 152–156 (review).

  • 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.

  • Knabbe C, Lippman ME, Wakefield LM, Flanders KC, Kasid A, Derynck R and Dickson RB . (1987). Cell, 48, 417–428.

  • Leitzel K, Teramoto Y, Konrad K, Chinchilli VM, Volas G, Grossberg H, Harvey H, Demers L and Lipton A . (1995). J. Clin. Oncol., 13, 1129–1135.

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

  • Lobenhofer EK, Huper G, Iglehart JD and Marks JR . (2000). Cell Growth Differ., 11, 99–110.

  • Mangelsdorf DJ and Evans RM . (1995). Cell, 83, 841–850 (review).

  • 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.

  • McDonnell DP, Clemm DL, Hermann T, Goldman ME and Pike JW . (1995). Mol. Endocrinol., 9, 659–669.

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

  • Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E and Auricchio F . (1996). EMBO J., 15, 1292–1300.

  • Molloy CA, May FE and Westley BR . (2000). J. Biol. Chem., 275, 12565–12571.

  • Muthuswamy SK, Gilman M and Brugge JS . (1999). Mol. Cell. Biol., 19, 6845–6857.

  • Nemere I and Farach-Carson MC . (1998). Biochem. Biophys. Res. Commun., 248, 443–449 (review).

  • Nicholson S, Wright C, Sainsbury JR, Halcrow P, Kelly P, Angus B, Farndon JR and Harris AL . (1990). J. Steroid Biochem. Mol. Biol., 37, 811–814.

  • Normanno N and Ciardiello F . (1997. J. Mammary Gland Biol. Neoplasia, 2, 143–151.

  • 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.

  • Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M and Yarden Y . (1996). EMBO J., 15, 2452–2467.

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

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

  • Reddy KB, Mangold GL, Tandon AK, Yoneda T, Mundy GR, Zilberstein A and Osborne CK . (1992). Cancer Res., 52, 3636–3641.

  • Reddy KB, Yee D, Hilsenbeck SG, Coffey RJ and Osborne CK . (1994). Cell Growth Differ., 5, 1275–1282.

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

  • Salomon DS and Kidwell WR . (1988). Cancer Treat Res., 40, 363–389 (review).

  • Salomon DS, Normanno N, Ciardiello F, Brandt R, Shoyab M and Todaro GJ . (1995). Breast Cancer Res. Treat., 33, 103–114 (review).

  • Salomon DS, Perroteau I, Kidwell WR, Tam J and Derynck R . (1987). J. Cell Physiol., 130, 397–409.

  • Sapino A, Pietribiasi F, Bussolati G and Marchisio PC . (1986). Cancer Res., 46, 2526–2531.

  • Scatchard G . (1949). Ann. NY Acad. Sci. USA, 51, 209–216.

  • Sepp-Lorenzino L, Eberhard I, Ma Z, Cho C, 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.

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

  • Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R and Santen RJ . (2002). Mol. Endocrinol., 16, 116–127.

  • Sporn MB and Roberts AB . (1985). Nature, 313, 745–747 (review).

  • Stancovski I, Hurwitz E, Leitner O, Ullrich A, Yarden Y and Sela M . (1991). Proc. Natl. Acad. Sci. USA, 88, 8691–8695.

  • 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, Katzenellenbogen BS and Martin MB . (2000c). Mol. Endocrinol., 14, 545–553.

  • Stoica EG, Franke TF, Wellstein A, Czubayko F, List HJ, Reiter R, Morgan E, Martin MB and Stoica A . (2003a). Mol. Endocrinol., 17, 818–830.

  • Stoica EG, Franke TF, Wellstein A, Morgan E, Czubayko F, List HJ, Reiter R, Martin MB and Stoica A . (2003b). Oncogene, 22, 2073–2087.

  • Sweeney CJ, Zhu J, Sandler AB, Schiller J, Belani CP, Langer C, Krook J, Harrington D and Johnson DH . (2001). Cancer, 92, 2639–2647.

  • Tandon AK, Clark GM, Chamness GC, Ullrich A and McGuire WL . (1989). J. Clin. Oncol., 7, 1120–1128.

  • Tsai MJ and O'Malley BW . (1994). Annu. Rev. Biochem., 63, 451–486 (review).

  • van der Geer P, Hunter T and Lindberg RA . (1994). Annu. Rev. Cell Biol., 10, 251–337 (review).

  • Vasudevan N, Kow LM and Pfaff DW . (2001). Proc. Natl. Acad. Sci. USA, 98, 12267–12271.

  • Vignon F, Bouton MM and Rochefort H . (1987). Biochem. Biophys. Res. Commun., 146, 1502–1508.

  • Vindelov LL, Christensen IJ and Nissen NI . (1983). Cytometry, 3, 323–327.

  • Waterman H, Alroy I, Strano S, Seger R and Yarden Y . (1999). EMBO J., 18, 3348–3358.

  • Watson CS and Gametchu B . (1999). Proc. Soc. Exp. Biol. Med., 220, 9–19 (review).

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

  • Wellstein A, Fang WJ, Khatri A, Lu Y, Swain SS, Dickson RB, Sasse J, Riegel AT and Lippman ME . (1992). J. Biol. Chem., 267, 2582–2587.

  • Wellstein A, Lupu R, Zugmaier G, Flamm SL, Cheville AL, Delli Bovi P, Basilico C, Lippman ME and Kern FG . (1990). Cell Growth Differ., 1, 63–71.

  • Wen Y, Hu MC, Makino K, Spohn B, Bartholomeusz G, Yan DH and Hung MC . (2000). Cancer Res., 60, 6841–6845.

  • Wosikowski K, Schuurhuis D, Kops GJ, Saceda M and Bates SE . (1997). Clin. Cancer Res., 3 (12 Partt 1), 2405–2414.

  • Wright C, Prasad K and Lennard TJ . (1992). J. Clin. Pathol., 45, 459–460.

  • Zeillinger R, Kury F, Czerwenka K, Kubista E, Sliutz G, Knogler W, Huber J, Zielinski C, Reiner G, Jakesz R, Staffen A, Reiner A, Wrba F and Spona Y . (1989). Oncogene, 4, 109–114.

  • Zhang K, Sun J, Liu N, Wen D, Chang D, Thomason A and Yoshinaga SK . (1996). J. Biol. Chem., 271, 3884–3890.

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Acknowledgements

We thank Drs S Byers and D Gamett for critically reading the manuscript. This work was supported by grants from 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, cell cycle analysis, microscopy, and imaging core facilities was provided by P50-CA-58185 and P30-CA-51008.

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Authors and Affiliations

  1. Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, 20057, DC, USA

    Gerald E Stoica, Maria Moroni, Susette Mueller, Ronald Reiter, Anton Wellstein, Mary Beth Martin & Adriana Stoica

  2. Department of Pharmacology, Columbia University, New York, 10032, USA

    Thomas F Franke

  3. School of Nursing and Health Studies, Georgetown University, Washington, 20057, DC, USA

    Elisha Morgan, Mary C Iann, Abigail D Winder & Adriana Stoica

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  1. Gerald E Stoica
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Correspondence to Adriana Stoica.

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Stoica, G., Franke, T., Moroni, M. et al. Effect of estradiol on estrogen receptor-α gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene 22, 7998–8011 (2003). https://doi.org/10.1038/sj.onc.1206769

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