ABSTRACT
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.
KEYWORDS
Non-genomic - signaling - proliferation and hormone resistance
REFERENCES
- 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
Email: rs5wf@virginia.edu
