Skip to main content

Advertisement

Springer Nature Link
Log in

Estrogen receptors outside the nucleus in breast cancer

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

Abstract

The estrogen receptor (ER) is the single most powerful predictor of breast cancer prognosis as well as an important contributor to the biology of carcinogenesis. In addition, endocrine therapy targeting ER directly (SERMS) or indirectly (aromatase inhibitors) forms the mainstay of adjuant therapy. Traditionally, human tumors are scored for the amount and presence of ER. However, this has centered on the population of ER found in the transformed epithelial cell nucleus. Over the last 40 years, it has been appreciated that additional cellular ER pools exist, in cytoplasm and at the plasma membrane. In this review, we discuss the important functions of extra-nuclear ER in breast cancer, including integration of function with nuclear ER.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Jensen EV, Jacobson HI (1962) Basic guides to the mechanism of estrogen action. Rec Prog Horm Res 18:387–414

    CAS  Google Scholar 

  2. Pietras R, Szego C (1979) Estrogen receptors in uterine plasma membrane. J Steroid Biochem 11:1471–1483

    PubMed  CAS  Google Scholar 

  3. Levin ER (2001) Cell Localization, physiology and nongenomic actions of estrogen receptors. J Appl Physiol 91:1860–1867

    PubMed  CAS  Google Scholar 

  4. Kushner PJ, Agard D, Feng WJ, Lopez G, Schiau A, Uht R, Webb P, Greene G (2000) Oestrogen receptor function at classical and alternative response elements. Novartis Found Symp 230:20–26

    Article  PubMed  CAS  Google Scholar 

  5. Mandava MB (1988) Plant growth-promoting brassinosteroids. Ann Rev Plant Physiol Plant Mol Biol 39:23–52

    CAS  Google Scholar 

  6. Wang ZY, Seto H, Fujioka S, Yoshida S, Chory J (2001) BRl1 is a critical component of a plasma-membrane receptor for plant steroids. Nature 410:380–383

    PubMed  CAS  Google Scholar 

  7. Qin C, Samudio I, Ngwenya S, Safe S (2004) Estrogen-dependent regulation of ornithine decarboxylase in breast cancer cells through activation of nongenomic cAMP-dependent pathways. Mol Carcinog 40:160–170

    PubMed  CAS  Google Scholar 

  8. Watters JJ, Chun TY, Kim YN, Bertics PJ, Gorski J (2000) Estrogen modulation of prolactin gene expression requires an intact mitogen-activated protein kinase signal transduction pathway in cultured rat pituitary cells. Mol Endocrinol 14:1872–1881

    PubMed  CAS  Google Scholar 

  9. Razandi M, Pedram A, Rosen E, Levin ER (2004) BRCA1 inhibits membrane estrogen and growth factor receptor signaling to cell proliferation in breast cancer. Mol Cell Biol 24:5900–5913

    PubMed  CAS  Google Scholar 

  10. Dowsett M, Nicholson R, Pietras R (2005) Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance. Breast Cancer Res Treat 93:S11–S118

    PubMed  CAS  Google Scholar 

  11. Coombes RC, Hall E, Gibson LJ et al for the Intergroup Exemestane Study (2004) A randomized trial of exemestane after two or three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092

    Google Scholar 

  12. Howell A, Cuzick J, Baum M et al for the ATAC Trialists’ Group (2005) Results of the ATAC (Arimidex, Tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62

    Google Scholar 

  13. ThŸrlimann B, Keshaviah A, Coates AS et al for the Breast International Group (BIG) 1–98 Collaborative Group (1975) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757

    Google Scholar 

  14. Pietras R, Szego C (1975) Endometrial cell calcium and oestrogen action. Nature 253: 357–359

    PubMed  CAS  Google Scholar 

  15. Pietras R, Szego C (1977) Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells. Nature 265:69–72

    PubMed  CAS  Google Scholar 

  16. Migliaccio A, Di Domenico M, Castoria G et al (1996) Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J 15:1292–1300

    PubMed  CAS  Google Scholar 

  17. Nemere I, Farach-Carson M (1998) Membrane receptors for steroid hormones: a case for specific cell surface binding sites for vitamin D metabolites and estrogens. Biochem Biophys Res Commun 248:443–449

    PubMed  CAS  Google Scholar 

  18. Kelly M, Levin E (2001) Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab 12:152–156

    PubMed  CAS  Google Scholar 

  19. Pietras R, Nemere I, Szego C (2001) Steroid hormone receptors in target cell membranes. Endocrine 14:417–427

    PubMed  CAS  Google Scholar 

  20. Levin E (2005) Integration of the extra-nuclear and nuclear actions of estrogen. Mol Endocrinol 19:1951–1959

    PubMed  CAS  Google Scholar 

  21. Pietras R, Marquez D, Chen H-W et al (2005) Estrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. Steroids 70:372–381

    PubMed  CAS  Google Scholar 

  22. Green S, Walter P, Kumar V et al (1986) Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 320:134–139

    PubMed  CAS  Google Scholar 

  23. Li L, Haynes M, Bender J (2003) Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Proc Natl Acad Sci 100:4807–4812

    PubMed  CAS  Google Scholar 

  24. Marquez D, Chen H-W, Curran E et al (2006) Estrogen receptors in membrane lipid rafts and signal transduction in breast cancer. Mol Cell Endocrinol 246:91–100

    PubMed  CAS  Google Scholar 

  25. Kim R, Kaneko M, Arhiro K et al (2006) Extranuclear expression of hormone receptors in primary breast cancer. Ann Oncol 17:1213–1220

    PubMed  CAS  Google Scholar 

  26. Pietras R, Szego C (1980) Partial purification and characterization of oestrogen receptors in subfractions of hepatocyte plasma membrane. Biochem J 191:743–760

    PubMed  CAS  Google Scholar 

  27. Pappas TC, Gametchu B, Yannariello-Brown J, Collins TJ, Watson CS (1995) Membrane estrogen receptors identified by multiple antibody labeling and impeded ligand binding. FASEB J 9:404–410

    PubMed  CAS  Google Scholar 

  28. Norfleet AM, Thomas ML, Gametchu B, Watson CS (1999) Estrogen receptor-alpha detected on the plasma membrane of aldehyde-fixed GH3/B6/F10 rat pituitary tumor cells by enzyme-linked immunocytochemistry. Endocrinology 140:3805–3814

    PubMed  CAS  Google Scholar 

  29. Razandi M, Pedram A, Greene GL, Levin ER (1999) Cell membrane and nuclear estrogen receptors derive from a single transcript: studies of ERα and ERβ expressed in CHO cells. Mol Endocrinol 13:307–319

    PubMed  CAS  Google Scholar 

  30. Chambliss KL, Yuhanna IS, Anderson RG, Mendelsohn ME, Shaul PW (2002) ERbeta has nongenomic action in caveolae. Mol Endocrinol 16:938–946

    PubMed  CAS  Google Scholar 

  31. Stabile L, Davis A, Gubish C, Hopkins T et al (2002) Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res 62:2141–2150

    PubMed  CAS  Google Scholar 

  32. Razandi M, Pedram A, Merchenthaler I, Greene GL, Levin ER (2004) Plasma membrane estrogen receptors exist and function as dimers. Mol Endocrinol 18:2854–2865

    PubMed  CAS  Google Scholar 

  33. Xiang R, Shi Y, Dillon D et al (2004) 2D LC/MS analysis of membrane proteins from breast cancer cell lines MCF7 and BT474. J Proteome Res 3:1278–1283

    PubMed  CAS  Google Scholar 

  34. Pedram A, Razandi M, Levin E (2006) Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol 20:1996–2006

    PubMed  CAS  Google Scholar 

  35. Nakhla AM, Romas NA, Rosner W (1997) Estradiol activates the prostate androgen receptor and prostate-specific antigen secretion through the intermediacy of sex hormone binding globulin. J Biol Chem 272:6838–6841

    PubMed  CAS  Google Scholar 

  36. Singh M, Setalo G Jr, Guan X, Warren M, Toran-Allerand CD (1999) Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J Neurosci 19:1179–1188

    PubMed  CAS  Google Scholar 

  37. Filippi S, Luconi M, Granchi S, Vignozzi L, Bettuzzi S, Tozzi P, Ledda F, Forti G, Maggi M (2002) Estrogens, but not androgens, regulate expression and functional activity of oxytocin receptor in rabbit epididymis. Endocrinology 143:4271–4280

    PubMed  CAS  Google Scholar 

  38. Wyckoff MH, Chambliss KL, Mineo C, Yuhanna IS, Mendelsohn ME, Mumby SM, Shaul PW (2001) Plasma membrane estrogen receptors are coupled to endothelial nitric-oxide synthase through Galpha(i). J Biol Chem 276:27071–27076

    PubMed  CAS  Google Scholar 

  39. Kelly MJ, Qiu J, Wagner EJ, Ronnekleiv OK (2002) Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS). J Steroid Biochem Mol Biol 83:187–193

    PubMed  CAS  Google Scholar 

  40. Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER (2002) Estrogen receptors associate with and regulate the production of caveolin: Implications for signaling and cellular actions. Mol Endocrinol 16:100–115

    PubMed  CAS  Google Scholar 

  41. Wong CW, McNally C, Nickbarg E, Komm BS, Cheskis BJ (2002) Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade. Proc Natl Acad Sci 99:14783–14788

    PubMed  CAS  Google Scholar 

  42. Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ (2004) The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane. Proc Natl Acad Sci 101:2076–2081

    PubMed  CAS  Google Scholar 

  43. Marquez D, Lee J, Lin T, Pietras R (2001) Epidermal growth factor receptor and tyrosine phosphorylation of estrogen receptor. Endocrine 16:73–81

    PubMed  CAS  Google Scholar 

  44. Pietras R, Arboleda J, Reese D et al (1995) HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 10:2435–2446

    PubMed  CAS  Google Scholar 

  45. Kim HP, Lee JY, Jeong JK, Bae SW, Lee HK, Jo I (1999) Non-genomic stimulation of nitric oxide release by estrogen is mediated by estrogen receptor alpha localized in caveolae. Biochem Biophys Res Commun 263:257–262

    PubMed  CAS  Google Scholar 

  46. Benten WP, Stephan C, Lieberherr M, Wunderlich F (2001) Estradiol signaling via sequestrable surface receptors. Endocrinology 142:1669–1677

    PubMed  CAS  Google Scholar 

  47. Pietras RJ, Szego C (1984) Specific internalization of estrogen and binding to nuclear matrix in isolated uterine cells. Biochem Biophys Res Comun 123:84–91

    CAS  Google Scholar 

  48. Hitosugi T, Sasaki K, Sato M, Suzuki Y, Umezawa Y (2007) EGF directs sex-specific steroid signaling through Src activation. J Biol Chem 282:10697–10706

    PubMed  CAS  Google Scholar 

  49. Stevis PE, Deecher DC, Suhadolnik L, Mallis LM, Frail DE (1999) Differential effects of estradiol and estradiol-BSA conjugates. Endocrinology 140:5455–5458

    PubMed  CAS  Google Scholar 

  50. Harrington WR, Kim SH, Funk CC, Madak-Erdogan Z, Schiff R, Katzenellenbogen JA, Katzenellenbogen BS (2006) Estrogen dendrimer conjugates that preferentially activate extra-nuclear, nongenomic versus genomic pathways of estrogen action. Mol Endocrinol 20:491–502

    PubMed  CAS  Google Scholar 

  51. Kim SH, Katzenellenbogen JA (2006) Hormone-PAMAM dendrimer conjugates: polymer dynamics and tether structure affect ligand access to receptors. Angew Chem Int Ed Engl 45:7243–7248

    PubMed  CAS  Google Scholar 

  52. Filardo EJ, Quinn JA, Frackelton AR Jr, Bland KI (2002) Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol Endocrinol 16:70–84

    PubMed  CAS  Google Scholar 

  53. Maggiolini M, Vivacqua A, Fasanella G, Recchia AG, Sisci D, Pezzi V, Montanaro D, Musti AM, Picard D, Ando S (2004) The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17-Estradiol and phytoestrogens in breast cancer cells. J Biol Chem 279:27008–27016

    PubMed  CAS  Google Scholar 

  54. Ahola TM, Manninen T, Alkio N, Ylikomi T (2002) G protein-coupled receptor 30 is critical for a progestin-induced growth inhibition in MCF-7 breast cancer cells. Endocrinology 143:3376–3384

    PubMed  CAS  Google Scholar 

  55. Thomas P, Pang Y, Filardo EJ, Dong J (2004) Identity of an estrogen membrane receptor coupled to a G-protein in human breast cancer cells. Endocrinology 164:624–632

    Google Scholar 

  56. Albanito L, Madeo A, Lappano R et al (2007) G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17β-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Can Res 67:1859–1866

    CAS  Google Scholar 

  57. Vivacqua A, Bonofiglio D, Recchia AG et al (2006) The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17β-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol Endocrinol 20:631–646

    PubMed  CAS  Google Scholar 

  58. Sukocheva O, Wadham C, Holmes A et al (2006) Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1. J Cell Biol 173:301–310

    PubMed  CAS  Google Scholar 

  59. Razandi M, Pedram A, Levin ER (2000) Estrogen signals to preservation of endothelial cell form and function. J Biol Chem 275:38540–38546

    PubMed  CAS  Google Scholar 

  60. Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH (2004) Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha. Proc Natl Acad Sci 101:17126–1731

    PubMed  CAS  Google Scholar 

  61. Razandi M, Alton G, Pedram A, Ghonshani S, Webb D, Levin ER (2003) Identification of a structural determinant for the membrane localization of ERα. Mol Cell Biol 23:1633–1646

    PubMed  CAS  Google Scholar 

  62. Chambliss KL, Simon L, Yuhanna IS, Mineo C, Shaul PW (2005) Dissecting the basis of nongenomic activation of eNOS by estradiol: role of ER domains with known nuclear functions. Mol Endocrinol 19:277–289

    PubMed  CAS  Google Scholar 

  63. Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ (2002) Linkage of rapid estrogen action to MAPK activation by ER alpha-shc association and shc pathway activation. Mol Endocrinol 16:116–127

    PubMed  CAS  Google Scholar 

  64. Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M (2004) S-palmitoylation modulates human estrogen receptor-alpha functions. Biochem Biophys Res Commun 316:878–883

    PubMed  CAS  Google Scholar 

  65. Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, Visca P, Marino M (2004) Palmitoylatin-dependent estrogen receptor (alpha) membrane localization regulation by 17 (beta)-estradiol. Mol Biol Cell 16:231–237

    PubMed  Google Scholar 

  66. Li L, Haynes MP, Bender JR (2003) Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Proc Natl Acad Sci 100:4807–4812

    PubMed  CAS  Google Scholar 

  67. Marquez-Garban D, Chen H-W, Weinberg O, Fishbein M, Pietras R (2005) Palmitoylation and membrane association of estrogen receptors in human breast and non-small cell lung cancer cells. Proceedings Endocrine Society, San Diego, CA, 651 (abstract)

  68. Pedram A, Razandi M, Sainson RCA, Kim JK, Hughes CC, Levin ER (2007) A conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem (in press)

  69. Zhang Z, Maier B, Santen RJ, Song RX (2002) Membrane association of estrogen receptor alpha mediates estrogen effect on MAPK activation. Biochem Biophys Res Commun 294:926–933

    PubMed  CAS  Google Scholar 

  70. Kousteni S, Han L, Chen JR, Almeida M, Plotkin LI, Bellido T, Manolagas SC (2003) Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest 111:1651–1664

    PubMed  CAS  Google Scholar 

  71. Keshamouni VG, Mattingly RR, Reddy KB (2002) Mechanism of 17-β estradiol-induced Erk 1,2 activation in breast cancer cells. A role for HER-2 and PKC-δ. J Biol Chem 277:22558–22565

    PubMed  CAS  Google Scholar 

  72. Kahlert S, Nuedling S, van Eickels M, Vetter H, Meyer R, Grohe C (2000) Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway. J Biol Chem 275:18447–18453

    PubMed  CAS  Google Scholar 

  73. Kato S, Endoh H et al (1995) Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270:1491–1494

    PubMed  CAS  Google Scholar 

  74. Martin MB, Franke TF, Stoica GE, Chambon P, Katzenellenbogen BS, Stoica BA, McLemore MS, Olivo SE, Stoica A (2000) A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology 141:4503–4511

    PubMed  CAS  Google Scholar 

  75. Balasenthil S, Barnes CJ, Rayala SK, Kumar R (2004) Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells. FEBS Lett 567:243–247

    PubMed  CAS  Google Scholar 

  76. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    PubMed  CAS  Google Scholar 

  77. Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ (1997) CDK-independent activation of estrogen receptor by cyclin D1. Cell 88:405–415

    PubMed  CAS  Google Scholar 

  78. Lopez GN, Turck CW, Schaufele F, Stallcup MR, Kushner PJ (2001) Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity. J Biol Chem 276:22177–22182

    PubMed  CAS  Google Scholar 

  79. Iwase H (2003) Molecular action of the estrogen receptor and hormone dependency in breast cancer. Breast Cancer 10:89–96

    Article  PubMed  Google Scholar 

  80. Michalides R, Griekspoor A, Balkenende A et al (2004) Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer. Cancer Cell 5:597–605

    PubMed  CAS  Google Scholar 

  81. Yamakawa K, Arita J (2004) Cross-talk between the estrogen receptor-, protein kinase A-, and mitogen-activated protein kinase-mediated signaling pathways in the regulation of lactotroph proliferation in primary culture. J Steroid Biochem Mol Biol 88:123–130

    PubMed  CAS  Google Scholar 

  82. Jordan VC (2004) Selective estrogen receptor modulation: concept and consequences in cancer. Cancer Cell 5:207–213

    PubMed  CAS  Google Scholar 

  83. Duan R, Xie W, Li X, McDougal A, Safe S (2002) Estrogen regulation of c-fos gene expression through phosphatidylinositol-3-kinase-dependent activation of serum response factor in MCF-7 breast cancer cells. Biochem Biophys Res Commun 294:384–394

    PubMed  CAS  Google Scholar 

  84. Pedram A, Razandi M, Aitkenhead M, Hughes CCW, Levin ER (2002) Integration of the non-genomic and genomic actions of estrogen: membrane initiated signaling by steroid (MISS) to transcription and cell biology. J Biol Chem 277:50768–50775

    PubMed  CAS  Google Scholar 

  85. Gately S, Li WW (2004) Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 31:2–11

    PubMed  CAS  Google Scholar 

  86. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK (1998) The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci 95:13513–13518

    PubMed  CAS  Google Scholar 

  87. Liang J, Slingerland JM (2003) Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2:339–345

    PubMed  CAS  Google Scholar 

  88. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934

    PubMed  CAS  Google Scholar 

  89. Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–72

    PubMed  CAS  Google Scholar 

  90. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927

    PubMed  CAS  Google Scholar 

  91. Proud CG (2004) Role of mTOR signalling in the control of translation initiation and elongation by nutrients. Curr Top Microbiol Immunol 279:215–244

    PubMed  CAS  Google Scholar 

  92. Plotkin LI, Ignacio Aguirre J, Kousteni S, Manolagas SC, Bellido T (2004) Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of ERK activation. J Biol Chem 280:7317–7325

    PubMed  Google Scholar 

  93. Chen JR, Plotkin LI, Aguirre JI, Han L, Jilka RL, Kousteni S, Bellido T, Manolagas SC (2004) Transient versus sustained phosphorylation and nuclear accumulation of ERKs underlie anti- versus Pro-apoptotic effects of estrogens. J Biol Chem 280:4632–4638

    PubMed  Google Scholar 

  94. Meyer G, Feldman EL (2002) Signaling mechanisms that regulate actin-based motility processes in the nervous system. J Neurochem 83:490–503

    PubMed  CAS  Google Scholar 

  95. Simoncini T, Scorticati C, Mannella P et al (2006) Estrogen receptor alpha interacts with Galpha13 to drive actin remodeling and endothelial cell migration via the RhoA/Rho kinase/moesin pathway. Mol Endocrinol 20:1756–1771

    PubMed  CAS  Google Scholar 

  96. Kipp JL, Ramirez VD (2001) Effect of estradiol, diethylstilbestrol, and resveratrol on F0F1-ATPase activity from mitochondrial preparations of rat heart, liver, and brain. Endocrine 15:165–175

    PubMed  CAS  Google Scholar 

  97. Chen JQ, Delannoy M, Cooke C, Yager JD (2004) Mitochondrial localization of ERalpha and ERbeta in human MCF7 cells. Am J Physiol Endocrinol Metab 286:E1011–1022

    PubMed  CAS  Google Scholar 

  98. Yang SH, Liu R, Perez EJ et al (2004) Mitochondrial localization of estrogen receptor beta. Proc Natl Acad Sci 101:4130–4135

    PubMed  CAS  Google Scholar 

  99. Pedram A, Razandi M, Wallace D, Levin E (2006) Functional estrogen receptors in the mitochondria of breast cancer cells. Mol Biol Cell 1749:2125–2137

    Google Scholar 

  100. Osborne C, Schiff R (2005) Estrogen-receptor biology: continuing progress and therapeutic implications. J Clin Oncol 23:1616–1622

    PubMed  CAS  Google Scholar 

  101. Pietras R (2006) Biologic basis of sequential and combination therapies for hormone-responsive breast cancer. Oncologist 11:704–717

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  103. Weinberg O, Marquez-Garban D, Pietras R (2005) New approaches to reverse resistance to hormonal therapy in human breast cancer. Drug Resist Updat 8:219–233

    PubMed  CAS  Google Scholar 

  104. Johnston S, Martin L, Head J et al (2005) Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance. J Steroid Biochem Mol Biol 95:173–181

    PubMed  CAS  Google Scholar 

  105. Wright C, Nicholson S, Angus B et al (1992) Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer. Brit J Cancer 65:118–124

    PubMed  CAS  Google Scholar 

  106. Borg A, Baldetorp B, Ferno M et al (1994) ErbB2 amplifi-cation is associated with tamoxifen resistance in steroid-receptor positive breast cancer. Cancer Lett 81:137–143

    PubMed  CAS  Google Scholar 

  107. Leitzel K, Teramoto Y, Konrad K et al (1995) Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer. J Clin Oncol 13:1129–1135

    PubMed  CAS  Google Scholar 

  108. Benz C, Scott G, Sarup J et al (1993) Estrogen-dependent, tamoxifen-resistent tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24:85–92

    CAS  Google Scholar 

  109. Lipton A, Ali S, Leitzel K et al (2002) Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer. J Clin Oncol 20:1467–1472

    PubMed  CAS  Google Scholar 

  110. De Laurentis M, Arpino G, Massarelli E et al (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

    Google Scholar 

  111. Weigel N (1996) Steroid hormone receptors and their regulation by phosphorylation. Biochem J 319:657–667

    PubMed  CAS  Google Scholar 

  112. Stoica G, Franke T, Wellstein A et al (2003) Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Mol Endocrinol 17:818–830

    PubMed  CAS  Google Scholar 

  113. Fan P, Wang J, Santen RJ, Yue W (2007) Long-term treatment with tamoxifen facilitates translocation of estrogen receptor α out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. Cancer Res 67:1352–1360

    PubMed  CAS  Google Scholar 

  114. Pietras RJ, Marquez DC, Chen H-W et al (2003) Improved antitumor therapy with Herceptin and Faslodex for dual targeting of HER-2 and estrogen receptor signaling pathways in human breast cancers with over-expression of HER-2/neu gene. Breast Cancer Res Treat 82:12–13

    Google Scholar 

  115. Ellis M, Coop A, Singh B et al (2003) Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res 63:6523–6531

    PubMed  CAS  Google Scholar 

  116. Subbaramaiah K, Howe L, Port E et al (2006) HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism. Cancer Res 66:5504–5511

    PubMed  CAS  Google Scholar 

  117. Kinoshita Y, Chen S (2003) Induction of aromatase (CYP19) expression in breast cancer cells through a nongenomic action of estrogen receptor alpha. Cancer Res 63: 3546–3555

    PubMed  CAS  Google Scholar 

  118. Masamura S, Santner SJ, Heitjan DF et al (1995) Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab 80:2918–2925

    PubMed  CAS  Google Scholar 

  119. Santen RJ, Song RX, Zhang Z et al (2004) Adaptive hypersensitivity to estrogen: mechanism for sequential responses to hormonal therapy in breast cancer. Clin Cancer Res 10:337S–345S

    PubMed  CAS  Google Scholar 

  120. Witters I, Kumar R, Chinchilli V, Lipton A (1997) Enhanced antiproliferative activity of the combination of tamoxifen plus HER-2-neu antibody. Breast Cancer Res Treat 42:1–5

    PubMed  CAS  Google Scholar 

  121. Kunisue H, Kurebayashi J, Otsuki T et al (2000) Anti-HER-2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors and HER-2. Br J Cancer 82:46–51

    PubMed  CAS  Google Scholar 

  122. Nicholson R, Hutcheson I, Harper M et al (2001) Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer. Endocr Relat Cancer 8:175–182

    PubMed  CAS  Google Scholar 

  123. Ellis M (2004) Overcoming endocrine therapy resistance by signal transduction inhibition. Oncologist 9:20–26

    PubMed  CAS  Google Scholar 

  124. Peralba J, DeGraffenried L, Friedrichs W et al (2003) Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 9:2887–2892

    PubMed  CAS  Google Scholar 

  125. Ferrara N (2005) VEGF as a therapeutic target in cancer. Oncology 69 3:11–16

    Google Scholar 

  126. Pietras RJ (2003) Interactions between estrogen and growth factor receptors in human breast cancers and the tumor-associated vasculature. Breast J 9:361–373

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We regret the inability to cite many fine contributions to this scientific area due to space limitations. This work was supported by grants from the Veterans Administration Research Service and the National Institutes of Health (ERL) and funds from the National Cancer Institute, the US Army Breast Cancer Research Program and the Stiles Program in Integrative Oncology. We wish to thank our scientific partners, Ali Pedram, Mahnaz Razandi, Diana Marquez and Hsiao-Wang Chen for their dedicated and excellent work and advice.

Author information

Authors and Affiliations

  1. University of California, Irvine/VA Long Beach Healthcare System, VALBHS/5901 E. Seventh St. (11-111I), Long Beach, CA, 90822, USA

    Ellis R. Levin

  2. Division of Hematology and Oncology, UCLA Department of Medicine, UCLA Department of Medicine, 11-934 Factor Building, Los Angeles, CA, 90095-1678, USA

    Richard J. Pietras

Authors
  1. Ellis R. Levin
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Richard J. Pietras
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Ellis R. Levin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Levin, E.R., Pietras, R.J. Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Res Treat 108, 351–361 (2008). https://doi.org/10.1007/s10549-007-9618-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-007-9618-4

Keywords