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Estrogen signaling pathway and hormonal therapy

  • Special Feature
  • Current topics in endocrine therapy for breast cancer
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Abstract

Hormonal therapy, such as estrogen-targeting therapy, has undergone remarkable development in recent several years, using drugs such as LH–RH agonists, new SERMs and third-generation aromatase inhibitors. Several ongoing large-scale international clinical trials for hormonal therapy are establishing the standard protocol for treatments with these drugs. On the other hand, there have been attempts to predict the individual efficacy of hormonal therapy using classical molecular biomarkers such as ER and PgR. However, approximately one-third of ERα-positive patients do not respond to endocrine therapy, while some ERα-negative patients are responsive. These discrepancies may be due to the different estrogen-related intracellular signaling pathways in breast cancer cells. Furthermore, the ineffectiveness of hormonal therapy in some individuals (due to, for example, aromatase inhibitor resistance) may be caused by these mechanisms. In this paper, we discuss the molecular mechanisms of these different responses to hormonal therapies and their implications for the estrogen signaling pathway in breast cancer cells. Furthermore, we touch upon basic studies into predicting the efficacy of hormonal therapy and new strategies in this field.

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References

  1. Hayashi S, Eguchi H, Tanimoto K, Yoshida T, Omoto Y, Inoue A, et al. The expression and function of estrogen receptor α and β in human breast cancer and its clinical application. Endocr Relat Cancer. 2003;10:193–202.

    Article  PubMed  CAS  Google Scholar 

  2. Levin ER. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol. 2005;19:1951–9.

    Article  PubMed  CAS  Google Scholar 

  3. Björnström L, Sjöberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol. 2005;19:833–42.

    Article  PubMed  Google Scholar 

  4. Norman AW, Mizwicki MT, Norman DP. Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model. Nat Rev. 2004;3:27–41.

    CAS  Google Scholar 

  5. Osborne CK, Shou J, Massarweh S, Schiff R. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res. 2005;11:865s–70s.

    PubMed  CAS  Google Scholar 

  6. Le Goff P, Montano MM, Schodin DJ, Katzenellenbogen BS. Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. J Biol Chem. 1994;269:4458–66.

    PubMed  CAS  Google Scholar 

  7. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995;270:1491–4.

    Article  PubMed  CAS  Google Scholar 

  8. Smith CL, O’Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004;25:45–71.

    Article  PubMed  CAS  Google Scholar 

  9. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, et al. AIB1, a steroid receptor coactivtor amplified in breast and ovarian cancer. Science. 1997;277:965–8.

    Article  PubMed  CAS  Google Scholar 

  10. Brown AMC, Jeltsch JM, Roberts M, Chambon P. Activation of pS2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7. Proc Natl Acad Sci USA. 1984;81:6344–8.

    Article  PubMed  CAS  Google Scholar 

  11. Westley B and Rochefort H. A secreted glycoprotein induced by estrogen in human breast cancer cell lines. Cell. 1980;20:353–62.

    Article  Google Scholar 

  12. Inoue S, Orimo A, Hosoi T, et al. Genomic binding-site cloning reveals an estrogen-responsive gene that encodes a RING finger protein. Proc Natl Acad Sci USA. 1993;90:11117–21.

    Article  PubMed  CAS  Google Scholar 

  13. Inoue A, Omoto Y, Yamaguchi Y, Kiyama R, Hayashi S. Transcription factor EGR3 is involved in the estrogen-signaling pathway in breast cancer cell. J Mol Endocrinol. 2004;32:649–61.

    Article  PubMed  CAS  Google Scholar 

  14. Liu MM, Albanese C, Anderson CM, Hilty K, Webb P, Uht RM, et al. Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. J Biol Chem. 2002;277:24353–60.

    Article  PubMed  CAS  Google Scholar 

  15. Bruning JC, Lingohr P, Gillette J, Hanstein B, Avci H, Krone W, et al. Estrogen receptor-alpha and Sp1 interact in the induction of the low density lipoprotein-receptor. J Steroid Biochem Mol Biol. 2003;86:113–21.

    Article  PubMed  CAS  Google Scholar 

  16. Kalaitzidis D, Gilmore TD. Transcription factor cross-talk: the estrogen receptor and NF-kappaB. Trends Endocrinol Metab. 2005;16:46–52.

    Article  PubMed  CAS  Google Scholar 

  17. Kato S, Masuhiro Y, Watanabe M, Kobayashi Y, Takeyama K, Endoh H, et al. Molecular mechanism of a cross-talk between oestrogen and growth factor signalling pathways. Genes Cells. 2000;5:593–601.

    Article  PubMed  CAS  Google Scholar 

  18. Bunone G, Briand P-A, Miksicek RJ, Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 1996;15:2174–83.

    PubMed  CAS  Google Scholar 

  19. Amold SF, Obourn JD, Jaffe H, Notides AC. Ser 167 is the major estradiol-induced phosphorylation site on the human estrogen receptor. Mol Endocrinol. 1994;8:1208–14.

    Article  Google Scholar 

  20. Joel PB, Smith J, Sturgill TW, Fisher TL, Blenis J, Lannigan DA. pp90srk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Mol Cell Biol. 1998;18:1978–84.

    PubMed  CAS  Google Scholar 

  21. Rowan BG, Weigel NL, O’Malley BW. Phosphorylation of steroid receptor coactivator-1: indentification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. J Biol Chem. 2000;275:4475–83.

    Article  PubMed  CAS  Google Scholar 

  22. Mora J, Brown M. AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol. 2000;20:5041–7.

    Article  Google Scholar 

  23. Yamashita H, Nishino M, Kobayashi S, Ando Y, Sugiura H, Zhang Z, et al. Phosphorylation of estrogen receptor α serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer. Breast Cancer Res. 2005;7:753–64.

    Article  Google Scholar 

  24. Razandi M, Pedram A, Greene GL, Levin ER. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERα and ERβ expressed in Chinese hamster ovary cells. Mol Endocrinol. 1999;13:307–19.

    Article  PubMed  CAS  Google Scholar 

  25. Harrington WR, Kim SH, Funk CC, Madak-Erdogan Z, Schiff R, Katzenellenbogen JA, et al. Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action. Mol Endocrinol. 2005;20:491–502.

    Article  PubMed  Google Scholar 

  26. Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ. The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane. Proc Natl Acad Sci USA. 2004;101:2076–81.

    Article  PubMed  CAS  Google Scholar 

  27. Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cell. Endocrinol. 2004;146:624–32.

    Article  Google Scholar 

  28. Maggiolini M, Vivacqua A, Fasanella G, Recchia AG, Sisci D, Pezzi V, et al. The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17β-estradiol and phytoestrogens in breast cancer cells. J Biol Chem. 2004;279:27008–16.

    Article  PubMed  CAS  Google Scholar 

  29. Pedram A, Razandi M, Levin ER. Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol. 2006;20:1996–2009.

    Article  PubMed  CAS  Google Scholar 

  30. Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER. ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol Endocrinol. 2002;16:100–15.

    Article  PubMed  CAS  Google Scholar 

  31. Barletta F, Wong CW, McNally C, Komm BS, Katzenellenbogen B, Cheskis BJ. Characterization of the interactions of estrogen receptor and MNAR in the activation of cSrc. Mol Endocrinol. 2004;18:1096–108.

    Article  PubMed  CAS  Google Scholar 

  32. Acconcia F, Kumar R. Signaling regulation of genomic and nongenomic functions of estrogen receptors. Cancer Lett. 2005;238:1–14.

    Article  PubMed  Google Scholar 

  33. Kumar R, Wang RA, Mazumdar A, Talukder AH, Mandal M, Yang Z, et al. A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm. Nature. 2002;418:654–7.

    Article  PubMed  CAS  Google Scholar 

  34. Yang Z, Barnes CJ, Kumar R. Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor α in breast cancer cells. Clin Cancer Res. 2004;10:3621–8.

    Article  PubMed  CAS  Google Scholar 

  35. Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang AH, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6:17–32.

    Article  PubMed  CAS  Google Scholar 

  36. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–48.

    Article  PubMed  CAS  Google Scholar 

  37. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401.

    Article  PubMed  CAS  Google Scholar 

  38. O’Neill JS, Miller WR. Aromatase activity in breast adipose tissue from women with benign and malignant breast disease. Br J Cancer. 1987;56:601–4.

    PubMed  CAS  Google Scholar 

  39. Santen RJ, Santner SJ, Pauley RJ, Tait L, Kaseta J, Demers LM, et al. Estrogen production via the aromatase enzyme in breast carcinoma: which cell type is responsible? J Steroid Biochem Mol Biol. 1997;61:267–71.

    Article  PubMed  CAS  Google Scholar 

  40. Simpson ER, Davis SR. Minireview: aromatase and the regulation of estrogen biosynthesis-some new perspectives. Endocrinology. 2001;142:4589–94.

    Article  PubMed  CAS  Google Scholar 

  41. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al. ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365:60–2.

    Article  PubMed  CAS  Google Scholar 

  42. Yamaguchi Y, Takei H, Suemasu K, Kobayashi Y, Kurosumi M, Harada N, et al. Tumor–stromal interaction through the estrogen-signaling pathway in human breast cancer. Cancer Res. 2005;65:4653–62.

    Article  PubMed  CAS  Google Scholar 

  43. Inoue A, Yoshida N, Omoto Y, Oguchi S, Yamori T, Kiyama R, et al. Development of cDNA microarray for expression profiling of estrogen-responsive genes. J Mol Endocrinol. 2002;29:175–92.

    Article  PubMed  CAS  Google Scholar 

  44. Yoshida N, Omoto Y, Inoue A, Eguchi H, Kobayashi Y, Kurosumi M, et al. Prediction of prognosis of estrogen receptor-positive breast cancer with combination of selected estrogen-regulated genes. Cancer Sci. 2004;95:496–502.

    Article  PubMed  CAS  Google Scholar 

  45. Harvell DME, Spoelstra NS, Singh M, McManaman JL, Finlayson C, Phang T, Hunter L, Dye WW, Borges VF, Elias A, Horwitz KB, Richer JK. Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance. Breast Cancer Res Treat. 2008; in press.

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Authors and Affiliations

  1. Department of Molecular and Functional Dynamics, Laboratory Medicine and Sciences, Tohoku University Graduate School of Medicine, 2-1 Seiryou-machi, Aoba-ku, Sendai, 980-8575, Japan

    Shin-ichi Hayashi

  2. Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Saitama, 362-0806, Japan

    Yuri Yamaguchi

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  1. Shin-ichi Hayashi
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  2. Yuri Yamaguchi
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Correspondence to Shin-ichi Hayashi.

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Hayashi, Si., Yamaguchi, Y. Estrogen signaling pathway and hormonal therapy. Breast Cancer 15, 256–261 (2008). https://doi.org/10.1007/s12282-008-0070-z

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  • DOI: https://doi.org/10.1007/s12282-008-0070-z

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