Skip to main content

Advertisement

SpringerLink
Log in

Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The majority of breast cancers are estrogen responsive, but upon progression of disease other growth promoting pathways are activated, e.g., the ErbB receptor system. The present study focuses on resistance to the pure estrogen antagonist fulvestrant and strategies to treat resistant cells or even circumvent development of resistance. Limited effects were observed when targeting EGFR and ErbB2 with the monoclonal antibodies cetuximab, trastuzumab, and pertuzumab, whereas the pan-ErbB inhibitor CI-1033 selectively inhibited growth of fulvestrant resistant cell lines. CI-1033 inhibited Erk but not Akt signaling, which as well as Erk is important for antiestrogen resistant cell growth. Accordingly, combination therapy with CI-1033 and the Akt inhibitor SH-6 or the Protein Kinase C inhibitor RO-32-0432 was applied and found superior to single agent treatment. Further, the resistant cell lines were more sensitive to CI-1033 treatment when grown in the presence of fulvestrant, as withdrawal of fulvestrant restored signaling through the estrogen receptor α (ERα), partly overcoming the growth inhibitory effects of CI-1033. Thus, the resistant cells could switch between ERα and ErbB signaling for growth promotion. Although parental MCF-7 cell growth primarily depends on ERα signaling, a heregulin-1β induced switch to ErbB signaling rescued MCF-7 cells from the growth inhibition exerted by fulvestrant-mediated blockade of ERα signaling. This interplay between ERα and ErbB signaling could be abrogated by combined therapy targeting both receptor systems. Thus, the present study indicates that upon development of antiestrogen resistance, antiestrogen treatment should be continued in combination with signal transduction inhibitors. Further, upfront combination of endocrine therapy with pan-ErbB inhibition may postpone or even prevent development of treatment resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Brünner N, Frandsen TL, Holst-Hansen C, Bei M, Thompson EW, Wakeling AE, Lippman ME, Clarke R (1993) MCF7/LCC2: a 4-hydroxytamoxifen resistant human breast cancer variant that retains sensitivity to the steroidal antiestrogen ICI 182, 780. Cancer Res 53:3229–3232

    PubMed  Google Scholar 

  2. Lykkesfeldt AE, Madsen MW, Briand P (1994) Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164, 384 and ICI 182, 780 sensitive human breast cancer cell line, MCF-7/TAMR-1. Cancer Res 54:1587–1595

    CAS  PubMed  Google Scholar 

  3. Howell A, DeFriend D, Robertson J, Blamey R, Walton P (1995) Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. Lancet 345:29–30

    Article  CAS  PubMed  Google Scholar 

  4. Osborne CK, Wakeling A, Nicholson RI (2004) Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer 90(Suppl 1):S2–S6

    Article  CAS  PubMed  Google Scholar 

  5. McClelland RA, Barrow D, Madden TA, Dutkowski CM, Pamment J, Knowlden JM, Gee JM, Nicholson RI (2001) Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182, 780 (Faslodex). Endocrinology 142:2776–2788

    Article  CAS  PubMed  Google Scholar 

  6. Atlas E, Cardillo M, Mehmi I, Zahedkargaran H, Tang C, Lupu R (2003) Heregulin is sufficient for the promotion of tumorigenicity and metastasis of breast cancer cells in vivo. Mol Cancer Res 1:165–175

    CAS  PubMed  Google Scholar 

  7. Sommer A, Hoffmann J, Lichtner RB, Schneider MR, Parczyk K (2003) Studies on the development of resistance to the pure antiestrogen faslodex in three human breast cancer cell lines. J Steroid Biochem Mol Biol 85:33–47

    Article  CAS  PubMed  Google Scholar 

  8. Frogne T, Jepsen JS, Larsen SS, Fog CK, Brockdorff BL, Lykkesfeldt AE (2005) Antiestrogen-resistant human breast cancer cells require activated protein kinase B/Akt for growth. Endocr Relat Cancer 12:599–614

    Article  CAS  PubMed  Google Scholar 

  9. Massarweh S, Osborne CK, Jiang S, Wakeling AE, Rimawi M, Mohsin SK, Hilsenbeck S, Schiff R (2006) Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer. Cancer Res 66:8266–8273

    Article  CAS  PubMed  Google Scholar 

  10. Fan M, Yan PS, Hartman-Frey C, Chen L, Paik H, Oyer SL, Salisbury JD, Cheng AS, Li L, Abbosh PH, Huang TH, Nephew KP (2006) Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res 66:11954–11966

    Article  CAS  PubMed  Google Scholar 

  11. Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV, Rasmussen LM, Riese DJ, de CP, Stenvang J, Lykkesfeldt AE (2009) Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat 114:263–275

    Article  CAS  PubMed  Google Scholar 

  12. Hobday TJ, Perez EA (2005) Molecularly targeted therapies for breast cancer. Cancer Control 12:73–81

    PubMed  Google Scholar 

  13. Stern DF (2008) ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer. J Mammary Gland Biol Neoplasia 13:215–223

    Article  PubMed  Google Scholar 

  14. Massarweh S, Schiff R (2006) Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. Endocr Relat Cancer 13(Suppl 1):S15–S24

    Article  CAS  PubMed  Google Scholar 

  15. Pancholi S, Lykkesfeldt AE, Hilmi C, Banerjee S, Leary A, Drury S, Johnston S, Dowsett M, Martin LA (2008) ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2. Endocr Relat Cancer 15:985–1002

    Article  CAS  PubMed  Google Scholar 

  16. Liu Y, el-Ashry D, Chen D, Ding IY, Kern FG (1995) MCF-7 breast cancer cells overexpressing transfected c-erbB-2 have an in vitro growth advantage in estrogen-depleted conditions and reduced estrogen-dependence and tamoxifen-sensitivity in vivo. Breast Cancer Res Treat 34:97–117

    Article  CAS  PubMed  Google Scholar 

  17. Stoica A, Saceda M, Doraiswamy VL, Coleman C, Martin MB (2000) Regulation of estrogen receptor-alpha gene expression by epidermal growth factor. J Endocrinol 165:371–378

    Article  CAS  PubMed  Google Scholar 

  18. Oh AS, Lorant LA, Holloway JN, Miller DL, Kern FG, el-Ashry D (2001) Hyperactivation of MAPK induces loss of ERalpha expression in breast cancer cells. Mol Endocrinol 15:1344–1359

    Article  CAS  PubMed  Google Scholar 

  19. Bayliss J, Hilger A, Vishnu P, Diehl K, el-Ashry D (2007) Reversal of the estrogen receptor negative phenotype in breast cancer and restoration of antiestrogen response. Clin Cancer Res 13:7029–7036

    Article  CAS  PubMed  Google Scholar 

  20. Houston SJ, Plunkett TA, Barnes DM, Smith P, Rubens RD, Miles DW (1999) Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 79:1220–1226

    Article  CAS  PubMed  Google Scholar 

  21. Arpino G, Weiss H, Lee AV, Schiff R, De PS, Osborne CK, Elledge RM (2005) Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 97:1254–1261

    Article  CAS  PubMed  Google Scholar 

  22. De Laurentiis M, Arpino G, Massarelli E, Ruggiero A, Carlomagno C, Ciardiello F, Tortora G, D’Agostino D, Caputo F, Cancello G, Montagna E, Malorni L, Zinno L, Lauria R, Bianco AR, De PS (2005) A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res 11:4741–4748

    Article  PubMed  Google Scholar 

  23. Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell’Orto P, Del CB, Henriksen KL, Mastropasqua MG, Price KN, Mery E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thurlimann B, Coates AS, Viale G (2008) Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1–98 randomised trial. Lancet Oncol 9:23–28

    Article  CAS  PubMed  Google Scholar 

  24. Lykkesfeldt AE, Larsen SS, Briand P (1995) Human breast cancer cell lines resistant to pure anti-estrogens are sensitive to tamoxifen treatment. Int J Cancer 61:529–534

    Article  CAS  PubMed  Google Scholar 

  25. Slichenmyer WJ, Elliott WL, Fry DW (2001) CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol 28:80–85

    Article  CAS  PubMed  Google Scholar 

  26. Allen LF, Lenehan PF, Eiseman IA, Elliott WL, Fry DW (2002) Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer. Semin Oncol 29:11–21

    CAS  PubMed  Google Scholar 

  27. Nelson JM, Fry DW (2001) Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition. J Biol Chem 276:14842–14847

    Article  CAS  PubMed  Google Scholar 

  28. Allen LF, Eiseman IA, Fry DW, Lenehan PF (2003) CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer. Semin Oncol 30:65–78

    Article  CAS  PubMed  Google Scholar 

  29. Rixe O, Franco SX, Yardley DA, Johnston SR, Martin M, Arun BK, Letrent SP, Rugo HS (2009) A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer. Cancer Chemother Pharmacol. doi:10.1007/s00280-009-0975-z

  30. Lykkesfeldt AE, Sorensen EK (1992) Effect of estrogen and antiestrogens on cell proliferation and synthesis of secreted proteins in the human breast cancer cell line MCF-7 and a tamoxifen resistant variant subline, AL-1. Acta Oncol 31:131–138

    Article  CAS  PubMed  Google Scholar 

  31. Lundholt BK, Briand P, Lykkesfeldt AE (2001) Growth inhibition and growth stimulation by estradiol of estrogen receptor transfected human breast epithelial cell lines involve different pathways. Breast Cancer Res Treat 67:199–214

    Article  CAS  PubMed  Google Scholar 

  32. Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CFIII, Hynes NE (2003) The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A 100:8933–8938

    Article  CAS  PubMed  Google Scholar 

  33. Frankel LB, Lykkesfeldt AE, Hansen JB, Stenvang J (2007) Protein kinase C alpha is a marker for antiestrogen resistance and is involved in the growth of tamoxifen resistant human breast cancer cells. Breast Cancer Res Treat 104:165–179

    Article  CAS  PubMed  Google Scholar 

  34. Larsen SS, Madsen MW, Jensen BL, Lykkesfeldt AE (1997) Resistance of human breast-cancer cells to the pure steroidal anti-estrogen ICI 182, 780 is not associated with a general loss of estrogen-receptor expression or lack of estrogen responsiveness. Int J Cancer 72:1129–1136

    Article  CAS  PubMed  Google Scholar 

  35. Munzone E, Curigliano G, Rocca A, Bonizzi G, Renne G, Goldhirsch A, Nole F (2006) Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy. Breast Cancer Res 8:R4

    Article  PubMed  CAS  Google Scholar 

  36. Larsen SS, Egeblad M, Jaattela M, Lykkesfeldt AE (1999) Acquired antiestrogen resistance in MCF-7 human breast cancer sublines is not accomplished by altered expression of receptors in the ErbB-family. Breast Cancer Res Treat 58:41–56

    Article  CAS  PubMed  Google Scholar 

  37. Gee JM, Harper ME, Hutcheson IR, Madden TA, Barrow D, Knowlden JM, McClelland RA, Jordan N, Wakeling AE, Nicholson RI (2003) The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro. Endocrinology 144:5105–5117

    Article  CAS  PubMed  Google Scholar 

  38. Okubo S, Kurebayashi J, Otsuki T, Yamamoto Y, Tanaka K, Sonoo H (2004) Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182, 780) in breast cancer cells. Br J Cancer 90:236–244

    Article  CAS  PubMed  Google Scholar 

  39. Arteaga CL, Coronado E, Osborne CK (1988) Blockade of the epidermal growth factor receptor inhibits transforming growth factor alpha-induced but not estrogen-induced growth of hormone-dependent human breast cancer. Mol Endocrinol 2:1064–1069

    Article  CAS  PubMed  Google Scholar 

  40. Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, Ramos L, Gorman CM, Parker MG, Sliwkowski MX, Slamon DJ (1995) HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 10:2435–2446

    CAS  PubMed  Google Scholar 

  41. van Agthoven T, van Agthoven TL, Portengen H, Foekens JA, Dorssers LC (1992) Ectopic expression of epidermal growth factor receptors induces hormone independence in ZR-75-1 human breast cancer cells. Cancer Res 52:5082–5088

    PubMed  Google Scholar 

  42. Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, Shepard HM, Osborne CK (1992) Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24:85–95

    Article  CAS  PubMed  Google Scholar 

  43. Nicholson RI, McClelland RA, Gee JM, Manning DL, Cannon P, Robertson JF, Ellis IO, Blamey RW (1994) Transforming growth factor-alpha and endocrine sensitivity in breast cancer. Cancer Res 54:1684–1689

    CAS  PubMed  Google Scholar 

  44. Nicholson RI, McClelland RA, Gee JM, Manning DL, Cannon P, Robertson JF, Ellis IO, Blamey RW (1994) Epidermal growth factor receptor expression in breast cancer: association with response to endocrine therapy. Breast Cancer Res Treat 29:117–125

    Article  CAS  PubMed  Google Scholar 

  45. Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516

    Article  CAS  PubMed  Google Scholar 

  46. Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L, De PS, Osborne CK, Schiff R (2007) Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst 99:694–705

    Article  CAS  PubMed  Google Scholar 

  47. Moulder SL, Arteaga CL (2003) A phase I/II trial of trastuzumab and gefitinib in patients with metastatic breast cancer that overexpresses HER2/neu (ErbB-2). Clin Breast Cancer 4:142–145

    Article  CAS  PubMed  Google Scholar 

  48. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445:437–441

    Article  CAS  PubMed  Google Scholar 

  49. Fabian MA, Biggs WHIII, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329–336

    Article  CAS  PubMed  Google Scholar 

  50. Wakeling AE, Dukes M, Bowler J (1991) A potent specific pure antiestrogen with clinical potential. Cancer Res 51:3867–3873

    CAS  PubMed  Google Scholar 

  51. Nicholson RI, Hutcheson IR, Hiscox SE, Knowlden JM, Giles M, Barrow D, Gee JM (2005) Growth factor signalling and resistance to selective oestrogen receptor modulators and pure anti-oestrogens: the use of anti-growth factor therapies to treat or delay endocrine resistance in breast cancer. Endocr Relat Cancer 12(Suppl 1):S29–S36

    Article  CAS  PubMed  Google Scholar 

  52. Sabnis G, Schayowitz A, Goloubeva O, Macedo L, Brodie A (2009) Trastuzumab reverses letrozole resistance and amplifies the sensitivity of breast cancer cells to estrogen. Cancer Res 69:1416–1428

    Article  CAS  PubMed  Google Scholar 

  53. Xia W, Bacus S, Hegde P, Husain I, Strum J, Liu L, Paulazzo G, Lyass L, Trusk P, Hill J, Harris J, Spector NL (2006) A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci USA 103:7795–7800

    Article  CAS  PubMed  Google Scholar 

  54. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS (2009) Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2630–2637

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We gratefully acknowledge the excellent technical assistance from Inger Heiberg. This study was supported by grants from Danish Cancer Society, Danish Agency for Science Technology and Innovation 271-07-0409, and Beckett Foundation and Mrs. Astrid Thaysen’s Foundation for Basic Medical Research.

Author information

Authors and Affiliations

  1. Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, 2100, Copenhagen, Denmark

    Katrine Sonne-Hansen, Ida C. Norrie, Kristina B. Emdal, Rikke V. Benjaminsen, Thomas Frogne, Tove Kirkegaard & Anne E. Lykkesfeldt

  2. Finsen Laboratory, Copenhagen Biocenter, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark

    Ib J. Christiansen

Authors
  1. Katrine Sonne-Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ida C. Norrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristina B. Emdal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rikke V. Benjaminsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas Frogne
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ib J. Christiansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tove Kirkegaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anne E. Lykkesfeldt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne E. Lykkesfeldt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sonne-Hansen, K., Norrie, I.C., Emdal, K.B. et al. Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance. Breast Cancer Res Treat 121, 601–613 (2010). https://doi.org/10.1007/s10549-009-0506-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0506-y

Keywords

Search

Navigation