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Phosphatidylinositol 3-Kinase/AKT-mediated Activation of Estrogen Receptor α

A NEW MODEL FOR ANTI-ESTROGEN RESISTANCE*
Open AccessPublished:March 30, 2001DOI:https://doi.org/10.1074/jbc.M010840200
      Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ERα in the absence of estrogen. Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERα, AKT increased the activity of only AF-1. PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKT-dependent and AKT-independent pathways in activating ERα. The consensus AKT phosphorylation site Ser-167 of ERα is required for phosphorylation and activation by AKT. In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ERα in vivo. Moreover, AKT overexpression led to up-regulation of estrogen-regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate that AKT protects breast cancer cells from tamoxifen-induced apoptosis. Taken together, these results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERα, and inhibition of tamoxifen-induced apoptotic regression.
      ER
      estrogen receptor
      ERE
      estrogen response element
      4-HT
      4-hydroxytamoxifen
      IGF
      insulin-like growth factor
      MIC-1
      macrophage inhibitory cytokine-1
      AF
      activation function
      EGF
      epidermal growth factor
      MEM
      minimal essential medium
      DMEM
      Dulbecco's modified Eagle's medium
      FCS
      fetal calf serum
      MAPK
      mitogen-activated protein kinase
      PI
      phosphatidylinositol
      PR
      phenol red
      CAT
      chloramphenicol acetyltransferase
      GST
      glutathione S-transferase
      TK
      thymidine kinase
      RARE
      retinoic acid response element
      DBD
      DNA binding domain
      CCS
      charcoal/dextran-treated serum
      AB
      amino-terminal A/B region
      Estrogen-induced proliferation of mammary and uterine epithelial cells is primarily mediated by estrogen receptors (ERs),1 which belong to steroid/thyroid hormone superfamily of transcription factors (
      • Mangelsdorf D.J.
      • Thummel C.
      • Beato M.
      • Herrlich P.
      • Schutz G.
      • Umesono K.
      • Blumberg B.
      • Kastner P.
      • Mark M.
      • Chambon P.
      • Evans R.M.
      ). ERs, through their estrogen-independent and estrogen-dependent activation domains (AF-1 and AF-2, respectively), regulate transcription by recruiting coactivator proteins and interacting with the general transcriptional machinery (
      • Glass C.K.
      • Rosenfeld M.G.
      ). Tamoxifen, which functions as a cell type-specific anti-estrogen, competitively binds to ERα and inhibits estrogen-stimulated growth of mammary epithelial cells. Depending on the concentration of tamoxifen, growth-arrested cells undergo apoptosis within 24 h or after 72 h of tamoxifen treatment (
      • Bursch W.
      • Ellinger A.
      • Kienzl H.
      • Torok L.
      • Pandey S.
      • Sikorska M.
      • Walker R.
      • Hermann R.S.
      ). Although most ERα-positive breast cancers initially respond to tamoxifen therapy, tamoxifen-resistant tumors eventually develop (
      • Johnston S.R.
      ). It has been shown previously that growth factors such as epidermal growth factor (EGF), insulin-like growth factor (IGF-1), and heregulin confer estrogen-independent growth properties to ERα-positive breast cancer cells (
      • Lupu R.
      • Cardillo M.
      • Cho C.
      • Harris L.
      • Hijazi M.
      • Perez C.
      • Rosenberg K.
      • Yang D.
      • Tang C.
      ,
      • Kato S.
      • Endoh H.
      • Masuhiro Y.
      • Kitamoto T.
      • Uchiyama S.
      • Sasaki H.
      • Masushige S.
      • Gotoh Y.
      • Nishida E.
      • Kawashima H.
      • Metzger D.
      • Chambon P.
      ,
      • Lee A.V.
      • Yee D.
      ). It is suggested that EGF- and IGF-1-induced mitogen-activated protein kinase (MAPK) phosphorylates Ser-118 of ERα, increases the activity of AF-1, and confers hormone-independent growth (
      • Kato S.
      • Endoh H.
      • Masuhiro Y.
      • Kitamoto T.
      • Uchiyama S.
      • Sasaki H.
      • Masushige S.
      • Gotoh Y.
      • Nishida E.
      • Kawashima H.
      • Metzger D.
      • Chambon P.
      ). However, a recent study indicates that, although prolonged activation of MAPK is growth inhibitory in breast cancer cells, parallel activation of the PI 3-kinase/AKT pathway by EGF and IGF-1 is sufficient to overcome such inhibition (
      • Zimmermann S.
      • Moelling K.
      ). Therefore, these growth factors may utilize the PI 3-kinase/AKT pathway to activate ERα and confer hormone-independent growth.
      Growth factor-dependent survival of a wide variety of cultured cells types ranging from fibroblasts to neurons is dependent on PI 3-kinase pathway (
      • Datta S.R.
      • Brunet A.
      • Greenberg M.E.
      ). Growth factor-induced activation of transmembrane receptors (IGF-1, EGF, platelet-derived growth factor, basic fibroblast growth factor, and heregulin) results in recruitment of PI 3-kinase to the plasma membrane (
      • Datta S.R.
      • Brunet A.
      • Greenberg M.E.
      ). In the plasma membrane, PI 3-kinase promotes generation of 3′-phosphorylated phosphoinositides, which in turn bind to AKT. AKT bound to phosphoinositides is translocated from cytoplasm to the plasma membrane, where it is activated through phosphorylation. Apart from growth factors, estrogen also activates AKT by triggering the binding of ERα to the p85 regulatory subunit of PI 3-kinase (
      • Simoncini T.
      • Hafezi-Moghadam A.
      • Brazil D.P.
      • Ley K.
      • Chin W.W.
      • Liao J.K.
      ). However, induction of AKT by estrogen is cell type-specific, as it is not observed in MCF-7 breast cancer cells (
      • Dupont J.
      • Karas M.
      • LeRoith D.
      ). Activated AKT promotes cell survival by phosphorylating and modulating the activity of various transcription factors in the nucleus. The tumor suppressor PTEN gene, which dephosphorylates 3′-phosphorylated phosphoinositides in vivo, inhibits AKT activation (
      • Cantley L.C.
      • Neel B.G.
      ). Several clinical and laboratory observations prompted us to study whether ERα is the target of AKT and whether AKT protects breast cancer cells against tamoxifen-induced apoptosis. For example, PI 3-kinase and AKT amplification is observed in breast and ovarian cancer (
      • Shayesteh L.
      • Lu Y.
      • Kuo W.L.
      • Baldocchi R.
      • Godfrey T.
      • Collins C.
      • Pinkel D.
      • Powell B.
      • Mills G.B.
      • Gray J.W.
      ,
      • Nakatani K.
      • Thompson D.A.
      • Barthel A.
      • Sakaue H.
      • Liu W.
      • Weigel R.J.
      • Roth R.A.
      ,
      • Bellacosa A.
      • de Feo D.
      • Godwin A.K.
      • Bell D.W.
      • Cheng J.Q.
      • Altomare D.A.
      • Wan M.
      • Dubeau L.
      • Scambia G.
      • Masciullo V.
      • Ferrandiana G.
      • Panici P.B.
      • Mancuso S.
      • Neri G.
      • Testa J.R.
      ). Cowden disease patients, who have a germ line-inactivating PTEN mutation, display increased breast cancer risks (
      • Liaw D.
      • Marsh D.J.
      • Li J.
      • Dahia P.L.
      • Wang S.I.
      • Zheng Z.
      • Bose S.
      • Call K.M.
      • Tsou H.C.
      • Peacocke M.
      • Eng C.
      • Parsons R.
      ). Similarly, PTEN mutation is observed in endometrial cancer (
      • Tonks N.K.
      • Myers M.P.
      ). Moreover, IGF-1 and heregulin, whose overexpression correlates with tamoxifen resistance, activate AKT (
      • Lupu R.
      • Cardillo M.
      • Cho C.
      • Harris L.
      • Hijazi M.
      • Perez C.
      • Rosenberg K.
      • Yang D.
      • Tang C.
      ,
      • Lee A.V.
      • Yee D.
      ). Finally, serine at amino acid position 167 of ERα is a consensus AKT phosphorylation site (RXRXX(S/T)) (
      • Datta S.R.
      • Brunet A.
      • Greenberg M.E.
      ). In this report, we show that AKT phosphorylates Ser-167 of ERα and confers tamoxifen resistance.

      DISCUSSION

      In this report, we demonstrate that PI 3-kinase/AKT signaling pathway modulates ERα activity in vivo, which correlates with phosphorylation of Ser-167 by AKT in vitro. Recent studies indicate that estrogen promotes association of ERα with IGF-1 receptor and p85 subunit of PI 3-kinase in the plasma membrane, which leads to AKT activation (
      • Simoncini T.
      • Hafezi-Moghadam A.
      • Brazil D.P.
      • Ley K.
      • Chin W.W.
      • Liao J.K.
      ,
      • Kahlert S.
      • Nuedling S.
      • van Eickels M.
      • Vetter H.
      • Meyer R.
      • Grohe C.
      ). Our results suggest that AKT serves as a functional link between membrane-associated and nuclear ERα. By phosphorylating Ser-167, AKT may modulate coactivator:AF-1 and/or corepressor:AF-1 interactions in the nucleus. Consistent with this possibility, previous studies have shown that phosphorylation of Ser-118 of ERα alters both coactivator:AF-1 and corepressor:AF-1 interactions (
      • Endoh H.
      • Maruyama K.
      • Masuhiro Y.
      • Kobayashi Y.
      • Goto M.
      • Tai H.
      • Yanagisawa J.
      • Metzger D.
      • Hashimoto S.
      • Kato S.
      ,
      • Lavinsky R.M.
      • Jepsen K.
      • Heinzel T.
      • Torchia J.
      • Mullen T.M.
      • Schiff R.
      • Del-Rio A.L.
      • Ricote M.
      • Ngo S.
      • Gemsch J.
      • Hilsenbeck S.G.
      • Osborne C.K.
      • Glass C.K.
      • Rosenfeld M.G.
      • Rose D.W.
      ).
      AF-1 region of ERα contains phosphorylation sites for a number of kinases including MAPK and cyclin A/cdk2 (
      • Kato S.
      • Endoh H.
      • Masuhiro Y.
      • Kitamoto T.
      • Uchiyama S.
      • Sasaki H.
      • Masushige S.
      • Gotoh Y.
      • Nishida E.
      • Kawashima H.
      • Metzger D.
      • Chambon P.
      ,
      • Rogatsky I.
      • Trowbridge J.M.
      • Garabedian M.J.
      ,
      • Bunone G.
      • Briand P.A.
      • Miksicek R.J.
      • Picard D.
      ). Some of these sites are conserved between ERα and ERβ (
      • Kuiper G.G.
      • Enmark E.
      • Pelto-Huikko M.
      • Nilsson S.
      • Gustafsson J.A.
      ). However, AKT phosphorylation site is present only in ERα (
      • Kuiper G.G.
      • Enmark E.
      • Pelto-Huikko M.
      • Nilsson S.
      • Gustafsson J.A.
      ). ERs exist as homodimers as well as ERα·ERβ heterodimers, and these combinations have different affinity for EREs (
      • Pace P.
      • Taylor J.
      • Suntharalingam S.
      • Coombes R.C.
      • Ali S.
      ,
      • Hyder S.M.
      • Chiappetta C.
      • Stancel G.M.
      ). Therefore, induction of ERE containing genes upon activation of AKT may be cell type-dependent. Furthermore, regulation of ERα activity by AKT may be controlled by p90RSK1 as it can also phosphorylate Ser-167 (
      • Joel P.B.
      • Smith J.
      • Sturgill T.W.
      • Fisher T.L.
      • Blenis J.
      • Lannigan D.A.
      ). Finally, MAPK may indirectly control AKT-mediated activation of ERα as it can activate p90RSK1(
      • Frodin M.
      • Gammeltoft S.
      ).
      We observed up-regulation of pS2, MIC-1, and Bcl-2 but not c-Myc in CA-AKT-overexpressing cells (Fig. 5 B). These results suggest that the ability of AKT to induce ERE-containing genes is promoter context-dependent. Because 4-HT repressed pS2 but not MIC-1 and Bcl-2 expression in CA-AKT cells, promoter context may also play a role in determining the ability of 4-HT to suppress AKT-mediated activation of estrogen-responsive genes (Fig. 5 B and data not shown). Both pS2 and Bcl-2 are well characterized estrogen-regulated genes, whereas MIC-1 promoter is yet to be characterized. While induction of pS2 by estrogen requires an ERE (
      • Berry M.
      • Nunez A.M.
      • Chambon P.
      ), activation of Bcl-2 by estrogen requires a SP-1 binding site, cAMP response element-binding protein binding site, and an ERE in the Bcl-2 promoter (
      • Dong L.
      • Wang W.
      • Wang F.
      • Stoner M.
      • Reed J.C.
      • Harigai M.
      • Samudio I.
      • Kladde M.P.
      • Vyhlidal C.
      • Safe S.
      ,
      • Perillo B.
      • Sasso A.
      • Abbondanza C.
      • Palumbo G.
      ). Interestingly, cAMP response element-binding protein binding site is required for AKT-mediated increase in Bcl-2 (
      • Pugazhenthi S.
      • Nesterova A.
      • Sable C.
      • Heidenreich K.A.
      • Boxer L.M.
      • Heasley L.E.
      • Reusch J.E.
      ). Therefore, it is likely that the ability of 4-HT to repress AKT-mediated activation of ERE-containing promoters is determined by promoter elements other than ERE. Alternatively, AKT may activate certain ERE-containing promoters independent of ERα, which is not subject to repression by 4-HT. Additional experiments with dominant negative mutants of ERα (
      • Chien P.Y.
      • Ito M.
      • Park Y.
      • Tagami T.
      • Gehm B.D.
      • Jameson J.L.
      ,
      • de Haan G.
      • Chusacultanachai S.
      • Mao C.
      • Katzenellenbogen B.S.
      • Shapiro D.J.
      ) are essential to distinguish between these possibilities.
      Our results indicate that activation of the PI 3-kinase/AKT pathway leads to increased Bcl-2 expression, which correlates with 4-HT resistance in breast cancer cells. Consistent with our results, Her2/Neu-mediated 4-HT resistance in MCF-7 correlates with Bcl-2 overexpression (
      • Kumar R.
      • Mandal M.
      • Lipton A.
      • Harvey H.
      • Thompson C.B.
      ). However, the results of our cell culture studies are inconsistent with clinical observations that correlate high Bcl-2 expression with favorable response to tamoxifen therapy and prolonged disease-free intervals (
      • Elledge R.M.
      • Green S.
      • Howes L.
      • Clark G.M.
      • Berardo M.
      • Allred D.C.
      • Pugh R.
      • Ciocca D.
      • Ravdin P.
      • O'Sullivan J.
      • Rivkin S.
      • Martino S.
      • Osborne C.K.
      ). It is possible that Bcl-2 works in concert with additional anti-apoptotic proteins to confer tamoxifen resistance, which is in accordance with the proposal that overall level of Bcl-2 family anti-apoptotic proteins dictates cellular response to therapy (
      • Vander Heiden M.G.
      • Thompson C.B.
      ).
      The PI 3-kinase/AKT pathway is the major survival pathway for a wide variety of cultured cell types (
      • Datta S.R.
      • Brunet A.
      • Greenberg M.E.
      ). ERα may be the central element in this survival pathway, at least in certain cell types. Broader implications of our results are on endometrial cancers as well as on Cowden's disease patients, who show a 30–50% incidence of breast cancer in affected females (
      • Liaw D.
      • Marsh D.J.
      • Li J.
      • Dahia P.L.
      • Wang S.I.
      • Zheng Z.
      • Bose S.
      • Call K.M.
      • Tsou H.C.
      • Peacocke M.
      • Eng C.
      • Parsons R.
      ). In both neoplastic conditions, AKT activity is increased due to mutation of PTEN. The PI 3-kinase/AKT pathway, therefore, may be an ideal target for therapeutic intervention in these cancers.

      Acknowledgments

      We thank P. Chambon, S. Boswell, J. Dixon, D. Donner, R. Roth, and Y. C. Yang for various plasmids. We also thank J. Hawes for mass spectrometry and S. Rice for flow cytometry.

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