Semin Reprod Med 2007; 25(3): 187-197
DOI: 10.1055/s-2007-973431
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Membrane-Initiated Steroid Signaling Action of Estrogen and Breast Cancer

Robert X.-D Song1
  • 1Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
Further Information

Publication History

Publication Date:
20 April 2007 (online)


Although classical concepts had assigned priority to the nuclear-initiated steroid signaling pathway of estrogen receptor (ER), recent studies document that the ER also possesses the membrane-initiated steroid signaling (MISS) pathway. A small fraction of ER is associated with the cell membrane and mediates the rapid effects of estrogen. Unlike classical growth factor receptors, such as insulinlike growth factor 1 receptor and epidermal growth factor receptor, ER has no transmembrane and kinase domains. Instead, the initiating signals of MISS action of ER require a rapid formation of ER-centered protein complexes with many signaling molecules, leading to the activation of mitogen-activated protein kinase and Akt signaling pathways. In this review, we focus on the MISS action of ER and its role in the development of hormone resistance in breast cancer. A full understanding of the mechanisms, with the ultimate aim of abrogating specific steps, should lead to more targeted strategies for treatment of hormone-dependent breast cancer.


  • 1 Cavalieri E L, Rogan E G. An unified mechanism in the initiation of cancer.  Ann NY Acad Sci. 2002;  959 341-354
  • 2 Nemere I, Pietras R J, Blackmore P F. Membrane receptors for steroid hormones: signal transduction and physiological significance.  J Cell Biochem. 2003;  88 438-445
  • 3 Leclercq G, Lacroix M, Laios I, Laurent G. Estrogen receptor alpha: impact of ligands on intracellular shuttling and turnover rate in breast cancer cells.  Curr Cancer Drug Targets. 2006;  6 39-64
  • 4 Song R X, Kumar R. The role of adapter proteins in ER alpha membrane association and function. In: Watson CS The Identities of Membrane Steroid Receptors. Boston; Kluwer Academic Publishers 2003: 67-76
  • 5 Kim K, Thu N, Saville B, Safe S. Domains of estrogen receptor alpha (ERalpha) required for ERalpha/Sp1-mediated activation of GC-rich promoters by estrogens and antiestrogens in breast cancer cells.  Mol Endocrinol. 2003;  17 804-817
  • 6 Schwartz J A, Zhong L, Deighton-Collins S, Zhao C, Skafar D F. Mutations targeted to a predicted helix in the extreme carboxyl-terminal region of the human estrogen receptor-alpha alter its response to estradiol and 4-hydroxytamoxifen.  J Biol Chem. 2002;  277 13202-13209
  • 7 Saji S, Hirose M, Toi M. Clinical significance of estrogen receptor beta in breast cancer.  Cancer Chemother Pharmacol. 2005;  56(suppl 1) 21-26
  • 8 Li L, Haynes M P, Bender J R. Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells.  Proc Natl Acad Sci USA. 2003;  100 4807-4812
  • 9 Wang Z, Zhang X, Shen P, Loggie B W, Chang Y, Deuel T F. A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling.  Proc Natl Acad Sci USA. 2006;  103 9063-9068
  • 10 Acconcia F, Ascenzi P, Bocedi A et al.. Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol.  Mol Biol Cell. 2005;  16 231-237
  • 11 Revankar C M, Cimino D F, Sklar L A, Arterburn J B, Prossnitz E R. A transmembrane intracellular estrogen receptor mediates rapid cell signaling.  Science. 2005;  307 1625-1630
  • 12 Pedram A, Razandi M, Levin E R. Nature of functional estrogen receptors at the plasma membrane.  Mol Endocrinol. 2006;  20 1996-2009
  • 13 Hammes A, Andreassen T K, Spoelgen R et al.. Role of endocytosis in cellular uptake of sex steroids.  Cell. 2005;  122 751-762
  • 14 Catalano M G, Comba A, Fazzari A et al.. Sex steroid binding protein receptor (SBP-R) is related to a reduced proliferation rate in human breast cancer.  Breast Cancer Res Treat. 1997;  42 227-234
  • 15 Nethrapalli I S, Tinnikov A A, Krishnan V, Lei C D, Toran-Allerand C D. Estrogen activates mitogen-activated protein kinase in native, nontransfected CHO-K1, COS-7, and RAT2 fibroblast cell lines.  Endocrinology. 2005;  146 56-63
  • 16 Harrington W R, Kim S H, Funk C C et al.. Estrogen dendrimer conjugates that preferentially activate extranuclear, non-genomic versus genomic pathways of estrogen action.  Mol Endocrinol. 2005;  20 491-502
  • 17 Razandi M, Pedram A, Greene G L, Levin E R. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells.  Mol Endocrinol. 1999;  13 307-319
  • 18 Norfleet A M, Clarke C H, Gametchu B, Watson C S. Antibodies to the estrogen receptor-alpha modulate rapid prolactin release from rat pituitary tumor cells through plasma membrane estrogen receptors.  FASEB J. 2000;  14 157-165
  • 19 Song R X, McPherson R A, Adam L et al.. Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation.  Mol Endocrinol. 2002;  16 116-127
  • 20 Chen J Q, Delannoy M, Cooke C, Yager J D. Mitochondrial localization of ER{alpha} and ER{beta} in human MCF7 cells.  Am J Physiol Endocrinol Metab. 2004;  286 E1011-E1022
  • 21 Govind A P, Thampan R V. Membrane associated estrogen receptors and related proteins: localization at the plasma membrane and the endoplasmic reticulum.  Mol Cell Biochem. 2003;  253 233-240
  • 22 Duffy M J. Estrogen receptors: role in breast cancer.  Crit Rev Clin Lab Sci. 2006;  43 325-347
  • 23 Kato S, Sato T, Watanabe T et al.. Function of nuclear sex hormone receptors in gene regulation.  Cancer Chemother Pharmacol. 2005;  56(suppl 1) 4-9
  • 24 Kushner P J, Agard D, Feng W J et al.. Oestrogen receptor function at classical and alternative response elements.  Novartis Found Symp. 2000;  230 20-26
  • 25 Pietras R J, Szego C M. Partial purification and characterization of estrogen receptors in subfractions of hepatocyte plasma membranes.  Biochem J. 1980;  191 743-760
  • 26 Chambliss K L, Simon L, Yuhanna I S, Mineo C, Shaul P W. Dissecting the basis of nongenomic activation of endothelial nitric oxide synthase by estradiol: role of ER{alpha} domains with known nuclear functions.  Mol Endocrinol. 2005;  19 277-289
  • 27 Watters J J, Chun T Y, Kim Y N, Bertics P J, Gorski J. Estrogen modulation of prolactin gene expression requires an intact mitogen-activated protein kinase signal transduction pathway in cultured rat pituitary cells.  Mol Endocrinol. 2000;  14 1872-1881
  • 28 Cheskis B J. Regulation of cell signalling cascades by steroid hormones.  J Cell Biochem. 2004;  93 20-27
  • 29 Kahlert S, Nuedling S, van Eickels M, Vetter H, Meyer R, Grohe C. Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway.  J Biol Chem. 2000;  275 18447-18453
  • 30 Pietras R J. Interactions between estrogen and growth factor receptors in human breast cancers and the tumor-associated vasculature.  Breast J. 2003;  9 361-373
  • 31 Barletta F, Wong C W, McNally C, Komm B S, Katzenellenbogen B, Cheskis B J. Characterization of the interactions of estrogen receptor and MNAR in the activation of cSrc.  Mol Endocrinol. 2004;  18 1096-1108
  • 32 Levin E R. Cellular functions of plasma membrane estrogen receptors.  Steroids. 2002;  67 471-475
  • 33 O'Malley B W. A life-long search for the molecular pathways of steroid hormone action.  Mol Endocrinol. 2005;  19 1402-1411
  • 34 Edwards D P, Wardell S E, Boonyaratanakornkit V. Progesterone receptor interacting coregulatory proteins and cross talk with cell signaling pathways.  J Steroid Biochem Mol Biol. 2002;  83 173-186
  • 35 Migliaccio A, Castoria G, Di Domenico M et al.. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation.  EMBO J. 2000;  19 5406-5417
  • 36 Norman A W, Mizwicki M T, Norman D P. Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model.  Nat Rev Drug Discov. 2004;  3 27-41
  • 37 Castoria G, Migliaccio A, Bilancio A et al.. PI3-kinase in concert with Src promotes the S-phase entry of oestradiol- stimulated MCF-7 cells.  EMBO J. 2001;  20 6050-6059
  • 38 Song R X, Barnes C J, Zhang Z, Bao Y, Kumar R, Santen R J. 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 USA. 2004;  101 2076-2081
  • 39 Razandi M, Oh P, Pedram A, Schnitzer J, Levin E R. ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions.  Mol Endocrinol. 2002;  16 100-115
  • 40 Cabodi S, Moro L, Baj G et al.. p130Cas interacts with estrogen receptor {alpha} and modulates non-genomic estrogen signaling in breast cancer cells.  J Cell Sci. 2004;  117 1603-1611
  • 41 Superti-Furga G, Courtneidge S A. Structure-function relationships in Src family and related protein tyrosine kinases.  Bioessays. 1995;  17 321-330
  • 42 Peterson J E, Kulik G, Jelinek T, Reuter C WM, Shannon J A, Weber M J. Src phosphorylates the insulin-like growth factor type I receptor on the autophosphorylation sites: requirement for transformation by src.  J Biol Chem. 1996;  271 31562-31571
  • 43 Arnold S F, Obourn J D, Jaffe H, Notides A C. Phosphorylation of the human estrogen receptor on tyrosine 537 in vivo and by src family tyrosine kinases in vitro.  Mol Endocrinol. 1995;  9 24-33
  • 44 Arnold S F, Vorojeikina D P, Notides A C. Phosphorylation of tyrosine 537 on the human estrogen receptor is required for binding to an estrogen response element.  J Biol Chem. 1995;  270 30205-30212
  • 45 Simoncini T, Hafezi-Moghadam A, Brazil D P, Ley K, Chin W W, Liao J K. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase.  Nature. 2000;  407 538-541
  • 46 Wyckoff M H, Chambliss K L, Mineo C et al.. Plasma membrane estrogen receptors are coupled to endothelial nitric-oxide synthase through Galpha(i).  J Biol Chem. 2001;  276 27071-27076
  • 47 Vadlamudi R K, Wang R A, Mazumdar A et al.. Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor alpha.  J Biol Chem. 2001;  276 38272-38279
  • 48 Balasenthil S, Vadlamudi R K. Functional interactions between the estrogen receptor coactivator PELP1/MNAR and retinoblastoma protein.  J Biol Chem. 2003;  278 22119-22127
  • 49 Boonyaratanakornkit V, Scott M P, Ribon V et al.. Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases.  Mol Cell. 2001;  8 269-280
  • 50 Vanhaesebroeck B, Waterfield M D. Signaling by distinct classes of phosphoinositide 3-kinases.  Exp Cell Res. 1999;  253 239-254
  • 51 Lamothe B, Bucchini D, Jami J, Joshi R L. Interaction of p85 subunit of PI 3-kinase with insulin and IGF-1 receptors analysed by using the two-hybrid system.  FEBS Lett. 1995;  373 51-55
  • 52 Altschuler D, Yamamoto K, Lapetina E G. Insulin-like growth factor-1-mediated association of p85 phosphatidylinositol 3-kinase with pp 185: requirement of SH2 domains for in vivo interaction.  Mol Endocrinol. 1994;  8 1139-1146
  • 53 Yamamoto K, Altschuler D, Wood E, Horlick K, Jacobs S, Lapetina E G. Association of phosphorylated insulin-like growth factor-I receptor with the SH2 domains of phosphatidylinositol 3-kinase p85.  J Biol Chem. 1992;  267 11337-11343
  • 54 Renzoni D A, Pugh D J, Siligardi G et al.. Structural and thermodynamic characterization of the interaction of the SH3 domain from Fyn with the proline-rich binding site on the p85 subunit of PI3-kinase.  Biochemistry. 1996;  35 15646-15653
  • 55 Kousteni S, Bellido T, Plotkin L I et al.. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity.  Cell. 2001;  104 719-730
  • 56 Migliaccio A, Di Domenico M, Castoria G et al.. Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol- receptor complex in MCF-7 cells.  EMBO J. 1996;  15 1292-1300
  • 57 Razandi M, Pedram A, Park S T, Levin E R. Proximal events in signaling by plasma membrane estrogen receptors.  J Biol Chem. 2003;  278 2701-2712
  • 58 Pelicci G, Dente L, De Giuseppe A et al.. A family of Shc related proteins with conserved PTB, CH1 and SH2 regions.  Oncogene. 1996;  13 633-641
  • 59 Gonfloni S, Weijland A, Kretzschmar J, Superti-Furga G. Crosstalk between the catalytic and regulatory domains allows bidirectional regulation of Src.  Nat Struct Biol. 2000;  7 281-286
  • 60 Ma Y C, Huang J, Ali S, Lowry W, Huang X Y. Src tyrosine kinase is a novel direct effector of G proteins.  Cell. 2000;  102 635-646
  • 61 Ma Y C, Huang X Y. Novel regulation and function of Src tyrosine kinase.  Cell Mol Life Sci. 2002;  59 456-462
  • 62 Sato K, Nagao T, Kakumoto M et al.. Adaptor protein Shc is an isoform-specific direct activator of the tyrosine kinase c-Src.  J Biol Chem. 2002;  277 29568-29576
  • 63 McEwen B, Akama K, Alves S et al.. Tracking the estrogen receptor in neurons: implications for estrogen-induced synapse formation.  Proc Natl Acad Sci USA. 2001;  98 7093-7100
  • 64 Warner M, Gustafsson J A. Nongenomic effects of estrogen: why all the uncertainty?.  Steroids. 2006;  71 91-95
  • 65 Guo X, Razandi M, Pedram A, Kassab G, Levin E R. Estrogen induces vascular wall dilation: mediation through kinase signaling to nitric oxide and estrogen receptors alpha and beta.  J Biol Chem. 2005;  280 19704-19710
  • 66 Castoria G, Barone M V, Di Domenico M et al.. Non-transcriptional action of oestradiol and progestin triggers DNA synthesis.  EMBO J. 1999;  18 2500-2510
  • 67 Levin E R. Integration of the extra-nuclear and nuclear actions of estrogen.  Mol Endocrinol. 2005;  19 1951-1959
  • 68 Razandi M, Pedram A, Merchenthaler I, Greene G L, Levin E R. Plasma membrane estrogen receptors exist and functions as dimers.  Mol Endocrinol. 2004;  18 2854-2865
  • 69 Nicholson R I, Johnston S R. Endocrine therapy-current benefits and limitations.  Breast Cancer Res Treat. 2005;  93(suppl 1) S3-S10
  • 70 Santen R J, Song R X, Zhang Z, Yue W, Kumar R. Adaptive hypersensitivity to estrogen: mechanism for sequential responses to hormonal therapy in breast cancer.  Clin Cancer Res. 2004;  10 337S-345S
  • 71 Ellis M J, Tao Y, Young O et al.. Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole.  J Clin Oncol. 2006;  24 3019-3025
  • 72 Masamura S, Santner S J, Heitjan D F, Santen R J. Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells.  J Clin Endocrinol Metab. 1995;  80 2918-2925
  • 73 Santen R, Jeng M H, Wang J P et al.. Adaptive hypersensitivity to estradiol: potential mechanism for secondary hormonal responses in breast cancer patients.  J Steroid Biochem Mol Biol. 2001;  79 115-125
  • 74 Yue W, Wang J P, Conaway M, Masamura S, Li Y, Santen R J. Activation of the MAPK pathway enhances sensitivity of MCF-7 breast cancer cells to the mitogenic effect of estradiol.  Endocrinology. 2002;  143 3221-3229
  • 75 Jelovac D, Sabnis G, Long B J, Macedo L, Goloubeva O G, Brodie A M. Activation of mitogen-activated protein kinase in xenografts and cells during prolonged treatment with aromatase inhibitor letrozole.  Cancer Res. 2005;  65 5380-5389
  • 76 Martin L A, Farmer I, Johnston S R, Ali S, Marshall C J, Dowsett M. Enhanced ERalpha ERBB2 and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term oestrogen deprivation.  J Biol Chem. 2003;  278 30458-30468
  • 77 Knowlden J M, Hutcheson I R, Jones H E et al.. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells.  Endocrinology. 2003;  144 1032-1044
  • 78 Massarweh S, Osborne C K, Jiang S et al.. 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. 2006;  66 8266-8273
  • 79 Yang Z, Barnes C J, Kumar R. Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells.  Clin Cancer Res. 2004;  10 3621-3628
  • 80 Fan P, Wang J, Santen R J, Yue W. Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells.  Cancer Res. 2007;  67 1352-1360

Robert X.-D SongPh.D. 

Division of Endocrinology, University of Virginia Health Science Center

Charlottesville, VA 22908