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(ER) via Interaction between ER and PI3K1
Department of Pathology and Programs of Molecular Oncology and Drug Discovery, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612 [M. S., J. E. P., Z-q. Y., D. C., S. A. S., S. V. N., J. Q. C.]; Beijing Institute for Cancer Research, Beijing 100034, China [Y. Y. L.]; and Cancer Research Department, Berlex Biosciences, Richmond, California 94804 [R. I. F.]
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(ER) positive, which prompted us to examine whether AKT2 regulates ER activity. We found that constitutively activated AKT2 or AKT2 activated by epidermal growth factor or insulin-like growth factor-1 promotes the transcriptional activity of ER. This effect occurred in the absence or presence of estrogen. Activated AKT2 phosphorylates ER in vitro and in vivo, but it does not phosphorylate a mutant ER in which ser-167 was replaced by Ala. The PI3K inhibitor, wortmannin, abolishes both the phosphorylation and transcriptional activity of ER induced by AKT2. However, AKT2-induced ER activity was not inhibited by tamoxifen but was completely abolished by ICI 164,384, implicating that AKT2-activated ER contributes to tamoxifen resistance. Moreover, we found that ER binds to the p85 regulatory subunit of PI3K in the absence or presence of estradiol in epithelial cells and subsequently activates PI3K/AKT2, suggesting ER regulation of PI3K/AKT2 through a nontranscriptional and ligand-independent mechanism. These data indicate that regulation between the ER and PI3K/AKT2 pathway (ER-PI3K/AKT2-ER) may play an important role in pathogenesis of human breast cancer and could contribute to ligand-independent breast cancer cell growth. |
Introduction |
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3
induces a cascade of events, including the release of accessory proteins (e.g., the heat-shock proteins), increased nuclear retention, DNA binding, and the transcription of estrogen-responsive genes, such as cyclin D1, c-myc, cathepsin D, and transforming growth factor- that are known to stimulate mammary cell proliferation (1)
. ER is a member of a superfamily of nuclear receptors that act as transcription factors when bound to specific lipophilic hormones. In common with other steroid hormone receptors, the ER has a NH2-terminal domain with a hormone-independent transcriptional activation function (AF-1), a central DNA-binding domain, and a COOH-terminal ligand-binding domain with a hormone-dependent transcriptional activation function (AF-2; Refs. 2
, 3
). In addition to its ligand, estradiol, the ER is also activated by several nonsteroidal growth factors including EGF and IGF1 through their cell membrane receptors and cytoplasmic signaling pathways such as MAPK signal transduction pathway (3
, 4)
. Because of the role of ER in promoting the growth and progression of breast cancers, considerable efforts are devoted to development of reagents to functionally inactivate ER, so as to inhibit ER-mediated gene expression and cell proliferation. Antiestrogens such as tamoxifen and ICI 164,384 antagonize the effects of estrogens by competing with estrogen for binding to ER. Tamoxifen or its derivative 4-hydroxytamoxifen inhibits transcriptional activation by AF-2 but not AF-1 (5)
. ICI 164,384, on other hand, is a complete antagonist that blocks transcriptional activation by both AF-1 and AF-2 (6)
. However, approximately one-third of ER-positive breast cancers fail to respond to antiestrogen treatment, which is thought to result from growth factor-induced ER activity through activation of protein kinases resulting in phosphorylation of ER (7)
.
It has been well documented that phosphorylation of ER is essential for the activation of ER after stimulation with its ligand and nonsteroidal growth factors (EGF and IGF1). The phosphorylation of ER is observed at both serine and tyrosine residues. The serine residues are the predominant modified amino acids present in ER, and four of these (Ser-104, Ser-106, Ser-118, and Ser-167) are clustered in the NH2 terminus within the AF-1 region. Phosphorylation of ER at Ser-118 is mediated by the Ras/MAPK pathway; therefore, activation of the MAPK pathway enables ligand-independent transactivation of ER (4)
. There is evidence showing that Ser-167 is phosphorylated by several protein kinases, including casein kinase II and pp90rsk1, which is important for DNA binding and transcriptional activation (8
, 9)
. Phosphorylation of ER on tyrosine 537, which is required for ER dimerization and transactivation, by Src family tyrosine kinases in vitro has also been demonstrated. Moreover, protein kinase A has been shown to phosphorylate ER at Ser-236 and regulate its dimerization (10)
.
In addition, recent studies (11)
demonstrated that plasma membrane ER plays a crucial role in transducing cellular signals. It has been convincingly shown that ER activates G-protein-coupled receptor leading to the modulation of downstream pathways that have discrete cellular actions including membrane K+ and Ca2+ channel activation and induction of protein kinase C and protein kinase A kinase activity (11)
. A recent study (12)
demonstrated that estrogen activates p38 MAPK, resulting in the activation MAPK-protein kinase-2 and subsequent phosphorylation of heat shock protein 27. ER has been also shown to interact with IGF1R and induce IGF1R and extracellular signal-regulated kinase activation (13)
.
Akt, also called protein kinase B, has been identified as a direct target of PI3K (14)
. All of the three members, Akt/AKT1/PKB, AKT2/PKBß, and AKT3/PKB
, of this family are activated by growth factors in a PI3K-dependent manner (14, 15, 16)
. Numerous studies (17)
showed that the Akt pathway is critical for cell survival by phosphorylation of a number of downstream proteins including BAD, caspase-9, Forkhead transcription factors, IKK, Raf, and p21-activated protein kinase. Among Akt family members, AKT2 has been shown to be predominantly involved in human malignancies such as ovarian and pancreatic cancers (18, 19, 20)
. In this study, we demonstrate frequent activation of AKT2 and PI3K in human breast cancer. AKT2 phosphorylates ER at Ser-167 and activates ER-mediated transcription in a PI3K-dependent manner. ER binds to the p85 subunit of PI3K in epithelial cells and activates the PI3K/AKT2 pathway in an estrogen-independent manner.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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-negative epithelial HEK293 and COS7 cells and ER-positive MCF7 and BG-1 cells were cultured at 37°C and 5% CO2 in DMEM supplemented with 10% FCS. The cells were seeded in 60-mm Petri dishes at a density of 8 x 105 cells/dish. Transfections were performed by calcium phosphate DNA precipitation or Lipofectamine Plus (Life Technologies, Inc.).
Immunoprecipitation and Western Blotting Analysis.
The cells and frozen tumor tissues were lysed in a buffer containing 20 mM Tris-HCl (pH 7.5), 137 mM NaCl, 15% (volume for volume) glycerol, 1% NP40, 2 mM phenylmethylsulfonyl fluoride, 2 µg/ml aprotinin and leupeptin, 2 mM benzamidine, 20 mM NaF, 10 mM NaPPi, 1 mM sodium vanadate, and 25 mM ß-glycerol phosphate. Lysates were centrifuged at 12,000 x g for 15 min at 4°C before immunoprecipitation or Western blotting. The protein concentration in each tissue lysate was measured, and an equal amount of protein was analyzed for protein expression and enzyme activity. For immunoprecipitation, lysates were precleared with protein A-protein G (2:1) agarose beads at 4°C for 20 min. After removal of the beads by centrifugation, lysates were incubated with anti-AKT2 (Upstate Biotechnology) antibody in the presence of 30 µl of protein A-protein G (2:1) agarose beads for 2 h at 4°C. The beads were washed once with 50 mM Tris-HCl (pH 7.5)-0.5 M LiCl-0.5% Triton X-10, twice with PBS, and once with 10 mM Tris-HCl (pH 7.5)-10 mM MgCl2-10 mM MnCl2-1 mM DTT, all containing 20 mM ß-glycerol phosphate and 0.1 mM sodium vanadate. Immunoprecipitates were subjected to in vitro kinase assay or Western blotting analysis. Protein phosphorylation and expression were determined by probing Western blots of immunoprecipitates with anti-phospho-Akt-Ser473 (Cell Signaling) or anti-AKT2 antibody. Detection of antigen-bound antibody was carried out with the enhanced chemiluminescence Western Blotting Analysis System (Amersham).
In Vitro Protein Kinase Assay.
Akt kinase assay was performed as described previously (15)
. Briefly, the reaction was carried out in the presence of 10 µCi of [-32P]ATP (NEN) and 3 µM cold ATP in 30 µl of buffer containing 20 mM HEPES (pH 7.4), 10 mM MgCl2, 10 mM MnCl2, and 1 mM DTT using histone H2B as substrate. After incubation at room temperature for 30 min, the reaction was stopped by adding protein-loading buffer, and the mixture was separated in SDS-PAGE gels. Each experiment was repeated three times. The relative amounts of incorporated radioactivity were determined by autoradiography and quantitated with a Phosphorimager (Molecular Dynamics).
Immunohistochemistry.
Formalin-fixed, paraffin-embedded sections were subjected to antigen retrieval by boiling in 0.01 M sodium citrate buffer (pH 6.0) in a microwave oven after dewaxing and rehydration. The Vectastain ABC Kit for sheep IgG (Vector Laboratories) was used to immunostain the tissue sections with phospho-S473 Akt antibody (catalogue number 06-801-MN; Upstate Biotechnology). Endogenous peroxidase and biotin were blocked, and sections were incubated 1 h at room temperature with a 1:250 dilution of antibody to phospho-S473 Akt. The remainder of the staining procedure was performed according to the manufacturer’s instructions using diaminobenzidine tetrahydrochloride as the chromogen and hematoxylin for counterstaining. Primary antibody was replaced with an equal concentration of nonimmune sheep IgG on negative control sections.
PI3K Assay.
PI3K was immunoprecipitated from the tumor tissue lysates with pan-p85 antibody (Santa Cruz Biotechnology). The immunoprecipitates were washed once with cold PBS, twice with 0.5 M LiCl, 0.1 M Tris (pH 7.4), and finally with 10 mM Tris, 100 mM NaCl, 1 mM EDTA. The presence of PI3K activity in immunoprecipitates was determined by incubating the beads with reaction buffer containing 10 mM HEPES (pH 7.4), 10 mM MgCl2, 50 µM ATP, 20 µCi [-32P]ATP, and 10 µg of L-a-phosphatidylinositol-4,5-bis phosphate (PI-4,5-P2; BIOMOL) for 20 min at 25°C. The reactions were stopped by adding 100 µl of 1 M HCl. Phospholipids were extracted with 200 µl of CHCl3/methanol. Phosphorylated products were separated by TLC as described previously (21)
. The conversion of PI-4,5-P2 to PI-3,4,5-P3 was determined by autoradiography and quantitated by using a Phosphorimager. Average readings of the kinase activity 3-fold higher than that in normal ovarian tissue was considered as elevated PI3K activity.
Expression Constructs and GST Fusion Protein.
HA epitope-tagged constitutively active, wild-type, and dominant-negative AKT2 were prepared as described previously (21)
. The p110 and p85 of PI3K expression constructs were gifts from Dr. Julian Downward (Imperial Cancer Research Fund, London, United Kingdom). The mammalian expression construct of ER-S167A was kindly provided by Dr. Benita S. Katzenellenbogen (University of Illinois, Urbana, IL). The GST-ER and GST-ER-S167A were created by PCR and inserted into pcDNA3 and pEGX-4T (Pharmacia) vectors, respectively. GST-ER fusion proteins were purified as described previously (21)
.
In Vivo [32P]Pi Cell Labeling.
Transfected COS7 and nontransfected MCF7 cells were labeled with [32P]Pi (0.5 mCi/ml) in MEM without phosphate, serum, and phenol red for 4 h and lysed. ER was immunoprecipitated with monoclonal anti-ER or anti-myc antibody. The immunoprecipitates were separated on SDS-PAGE and transferred to membranes. Phosphorylated ER was detected by autoradiography and quantitated by using Molecular Dynamics Phosphorimager with ImageQuant software.
Reporter Assay.
HEK293 and MCF7 cells (8 x 105) were seeded in a 60-mm plate. The cells were cotransfected with the luciferase reporter plasmid (2ERE-MpG12), wild-type, constitutively active, or dominant-negative AKT2 and ER, as well as pCMV-ßgal plasmid as an internal control. The amount of DNA in each transfection was kept constant by the addition of empty pcDNA3 vector. Luciferase and ß-galactosidase activities were determined 48 h after transfection according to the manufacturer’s procedure (Promega). Luciferase activity was corrected for transfection efficiency by using the control ß-galactosidase activity. All of the experiments were performed in triplicate from independent cell cultures.
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Results and Discussion |
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. To further demonstrate AKT2 activation in breast cancer, we performed Western blot analyses of tumor lysates with phospho-Ser-473 antibody, a phosphorylation site that is critical for activation of three isoforms of Akt (17)
. To avoid the cross-reaction, the tumor lysates were incubated with anti-AKT2 antibody. The AKT2 immunoprecipitates were separated by SDS-PAGE and probed with phospho-Ser473 antibody. Phosphorylated AKT2 was detected only in breast tumors with elevated AKT2 kinase activity (Fig. 1A)
. Because stromal tissues account for approximately 20–30% of the tumor specimens used in this study, we examined whether the activation of AKT2 is derived from the tumor cells or the stromal tissues by immunostaining paraffin sections with a phospho-Ser473 Akt antibody. Positive staining of tumor cells was detected in all of the 32 cases with AKT2 activation, whereas no staining was observed in normal ductal epithelial cells (Fig. 1B)
. These data suggest that activation of AKT2 is a common occurrence in human breast cancer.
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, indicating that activation of AKT2 in breast cancer predominantly results from PI3K activation. Moreover, Western blot and immunohistochemistry analyses with anti-ER antibody revealed that 88% of the cases (28 of 32) with PI3K/AKT2 activation showed strong ER positive (Fig. 1, A and B)
, whereas only 54% of the cases (14 of 26) without PI3K/AKT2 activation exhibited positive ER, suggesting that activated PI3K/AKT2 could be involved in the regulation of ER activity in breast cancer cells. In addition, the majority of cases with AKT2 activation are late stage (23 of 32 at stages III and IV) and poorly differentiated tumors (19 of 32), indicating that PI3K/AKT2 activation in breast cancer may be associated with tumor progression rather than initiation.
AKT2 Activates ER-mediated Transcription in a Ligand-independent Manner.
Previous studies (1
, 25)
have shown that MAPK is activated in breast cancer and contributes to estrogen-independent breast tumor cell growth by direct phosphorylation of ER. Moreover, several other signal molecules, including protein kinase A, casein kinase II, pp90rsk1, and MEKK1/p38, have been shown to activate ER-mediated transcription, possibly resulting in hormone-independent tumor cell growth (1
, 8, 9, 10
, 26)
. Because AKT2 and PI3K are frequently activated in breast cancer and the majority of cases with AKT2 activation are ER positive, we investigated whether AKT2 and PI3K regulate ER-mediated transcription. ER-positive MCF7 breast cancer cells were transiently transfected with a reporter construct containing a luciferase gene regulated by two estrogen response elements (ERE2-TK-LUC) and a plasmid expressing ß-galactosidase that allows the luciferase data to be normalized for transfection efficiency. In addition, the cells were transfected with expression constructs for constitutively activated p110 (p110-K227E) subunit of PI3K, wild-type, constitutively activated, and dominant-negative AKT2 or vector alone. As shown in Fig. 2
, p110-K227E or myr-AKT2 increased ERE2-TK-LUC activity 3–4-fold in the absence of estradiol. Constitutively activated p110-induced reporter activity was attenuated by dominant-negative mutant AKT2 (Fig. 2A)
. Tamoxifen (4-hydroxytamoxifen), an antiestrogen reagent that inhibits transcriptional activation by AF2 but not through AF1 (5)
, abolished estradiol-enhanced transcription but had no effects on p110-K227E and myr-AKT2-stimulated ER activity (Fig. 2, A and B)
, suggesting that PI3K/AKT2-increased ER transcriptional activity is regulated by phosphorylation of ER within the AF1 region and could be involved in tamoxifen resistance.
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(6
, 27)
, completely blocked PI3K- and AKT2-induced reporter activity. PTEN, a tumor suppressor encoding a lipid phosphatase that negatively regulates PI3K, inhibited constitutively active p110-induced ER-mediated transcription but had no effect on constitutively activated AKT2-stimulated ER activity (Fig. 2B)
.
Moreover, we have observed that exogenous expression of ER in ER-positive MCF7 cells increased wild-type AKT2-induced ERE2-TK-LUC activity 2–3-fold as compared with cells transfected with wild-type AKT2 alone (Fig. 2C)
, implying that ER might activate AKT2 kinase and subsequently enhance its own transcriptional activity (see below). Taken collectively, these data indicate that PI3K/AKT2-activated ER-mediated transcription is estrogen-independent and that the frequently elevated level of PI3K/AKT2 kinase in primary breast cancer could relate the refractoriness of hormone therapy.
AKT2 Mediates Growth Factor-induced ER Transcriptional Activity.
A very recent study (28)
showed that Akt1 mediates the estrogenic functions of EGF and IGF1. Next, we examined the possible role of AKT2 in growth factor-induced ER activation. ER-positive MCF7 cells were transfected with ERE2-TK-LUC and dominant-negative, wild-type, or constitutively activated AKT2 or vector alone and were treated with or without either 100 ng/ml EGF or 50 ng/ml IGF1 (Fig. 2D)
. Treatment with the growth factors resulted in an approximately 4.5-fold increase in ER-mediated transcriptional activity. The EGF- and IGF1-induced reporter activity was partially abrogated by dominant-negative AKT2 or PI3K inhibitor LY294002 and completely blocked by the combination of PI3K and MAPK inhibitors (LY294002 and PD98059). However, the combined inhibitors had no effect on constitutively activated AKT2-induced reporter activity. These results suggest that the "steroid-independent activation" of ER by growth factors is mediated by the PI3K/AKT2 pathway, in addition to MAPK, PKA, casein kinase II, and pp90rsk1.
AKT2 Phosphorylated Serine-167 of ER in Vitro and in Vivo.
Phosphorylation of ER has been shown to be an important mechanism by which ER activity is regulated. ER is hyperphosphorylated on multiple sites in response to hormone binding and growth factor stimulation (1, 2, 3, 4)
. Transcriptional activation by growth factors has been shown to require AF-1 but not AF-2 (1
, 8, 9, 10)
. There is evidence to suggest that EGF and IGF-1 induce MAPK and pp90rsk1/casine kinase II activity leading to phosphorylation of serine-118 and serine-167, respectively, in AF-1 region (4
, 5
, 8, 9, 10)
. To examine whether AKT2 phosphorylates ER in vitro, HEK293 cells were transfected with HA-tagged wild-type and constitutively activated AKT2, and immunoprecipitation was prepared with anti-HA antibody. In vitro AKT2 kinase assays, using full length of human recombinant ER as substrate, revealed that constitutively activated AKT2 and EGF-induced AKT2 strongly phosphorylated hER. The ER phosphorylation that was induced by EGF-stimulated AKT2 was abrogated by wortmannin (Fig. 3A)
.
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in vivo, MCF7 cells were transfected with constitutively activated AKT2 or pcDNA3 vector alone and labeled with [32P]Pi. The cell lysates were incubated with anti-ER antibody, and the immunoprecipitates were separated on SDS-PAGE. ER was highly phosphorylated in constitutively activated AKT2-transfected cells but in the cells transfected with vector alone (Fig. 3C)
. These data indicate that AKT2 phosphorylated ER both in vitro and in vivo.
Martin et al. (28)
recently demonstrated that EGF- and IGF1-induced Akt1 potentiates the AF-1 function of ER, possibly through the phosphorylation of serine residues. There are four serine residues (Ser-104, Ser-106, Ser-118, and Ser-167) in the AF-1 region of the receptor that are predominantly phosphorylated in response to estrogen and growth factor stimulation (1, 2, 3, 4)
. We examined the ER protein sequence and found that serine-167 (162RERLAS167) is a putative AKT2 phosphorylation site. Constructs expressing GST-fused wild-type and mutant (S167A) AF-1 region were created. In vitro kinase assays revealed that myr-AKT2 and EGF-stimulated AKT2 strongly phosphorylated GST-ER-S167 but not GST-ER-S167A mutant (Fig. 3B)
. The EGF-induced AKT2 phosphorylation of ER is blocked by wortmannin. To examine whether AKT2 phosphorylates serine-167 in vivo, COS7 cells were transfected with myc-tagged wild-type and mutant (S167A) human ER expression constructs together with constitutively activated AKT2. After 36 h of transfection, the cells were incubated with [32P]Pi and immunoprecipitated with anti-myc antibody. As demonstrated in Fig. 3C
, constitutively active AKT2 phosphorylated wild-type ER but not the ER-S167A mutant in vivo, suggesting that serine-167 of ER is a physiological substrate for AKT2.
Previous studies (29)
showed that serine-167 is important for ER transcriptional activity. To further examine whether AKT2-activated ER transcriptional activity depends upon phosphorylation of serine-167, reporter assays were carried out in HEK293 cells transfected with ERE2-TK-LUC, constitutively activated AKT2, and ER-S167A or wild-type ER. Fig. 3D
shows that ER-S167A had no ability to mediate constitutively activated AKT2-induced ERE2-TK-LUC reporter activity, indicating that AKT2 regulates ER-mediated transcription through phosphorylation of serine-167.
ER Binds To and Activates PI3K/AKT2 in Epithelial Cells via a Ligand-independent Mechanism.
Recent studies (30
, 31)
demonstrated that ER binds to the p85 regulatory subunit of PI3K after estradiol treatment, leading to the activation of PI3K/Akt and endothelial nitric oxide synthase in endothelial cells. In the absence of estradiol, ER failed to bind and activate PI3K, indicating that ER-associated PI3K in endothelial cells is estrogen-dependent (30)
. Next, we examined whether ER binds to and activates PI3K/AKT2 in epithelial cells. ER/HA-p85-transfected HEK293 and nontransfected ER-positive MCF7 cells were immunoprecipitated with anti-ER and detected with anti-HA or anti-p85 antibody or vice versa. As shown in Fig. 4A and B
, ER constitutively associated with p85, and this interaction was unaffected by estradiol treatment. In addition, in vitro PI3K assays revealed that expression of ER in HEK 293 cells significantly induced PI3K activity in the absence or presence of estradiol (Fig. 4C)
. These data suggest that ER binding to and activating PI3K is ligand-independent in epithelial cells.
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activates AKT2 and whether this activation is dependent on AKT2 phosphorylation. ER-negative HEK293 cells were transfected with ER or ER-S167A, together with HA-AKT2. In vitro AKT2 kinase assays revealed that ER significantly activates AKT2 in the absence of estradiol. Additional estradiol treatment did not further enhance ER-induced AKT2 activation. The PI3K inhibitor, wortmannin, completely abolished the activation. Interestingly, ER-S167A activated AKT2 at a similar level to that of wild-type ER. Coexpression of myc-tagged constitutively active AKT2 (Myc-myr-AKT2) and ER had the same effect on wild-type AKT2 activation as that of expression of ER alone (Fig. 4D)
. These results indicate that activation of AKT2 by ER is through PI3K and independent of ER phosphorylation by PI3K/AKT2.
In summary, we demonstrate in this study that AKT2 and PI3K are frequently activated in primary human breast carcinoma. The PI3K/AKT2 pathway regulates ER transcriptional activity by phosphorylation of serine-167 in vitro and in vivo, and ER activates PI3K/AKT2 kinase by binding to p85 in a ligand-independent manner in epithelial cells. This study suggests that the PI3K/AKT2 pathway may play a pivotal role in estrogen-independent breast cancer cell growth and tamoxifen-resistance; therefore, it could represent an important therapeutic target in human breast cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Grants from NIH CA77935 and Department of Defense OC990075. 
2 To whom requests for reprints should be addressed, at Department of Pathology and Programs of Molecular Oncology and Drug Discovery, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12901 Bruce B. Downs Boulevard, MDC Box 11, Tampa, FL 33612. Phone: (813) 974-8595; Fax: (813) 974-5536; E-mail: jcheng{at}hsc.usf.edu
3 The abbreviations used are: ER, estrogen receptor ; PI3K, phosphatidylinositol-3-OH kinase; PKB, protein kinase B; MAPK, mitogen-activated protein kinase; HA, hemagglutinin; EGF, epidermal growth factor; IGF1, insulin-like growth factor-1; GST, glutathione S-transferase; HEK, human embryonic kidney.
Received 5/ 7/01. Accepted 7/15/01.
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K. Lehnes, A. D. Winder, C. Alfonso, N. Kasid, M. Simoneaux, H. Summe, E. Morgan, M. C. Iann, J. Duncan, M. Eagan, et al. The Effect of Estradiol on in Vivo Tumorigenesis Is Modulated by the Human Epidermal Growth Factor Receptor 2/Phosphatidylinositol 3-Kinase/Akt1 Pathway Endocrinology, March 1, 2007; 148(3): 1171 - 1180. [Abstract] [Full Text] [PDF]
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C. Verga Falzacappa, E. Petrucci, V. Patriarca, S. Michienzi, A. Stigliano, E. Brunetti, V. Toscano, and S. Misiti Thyroid hormone receptor TR{beta}1 mediates Akt activation by T3 in pancreatic {beta} cells J. Mol. Endocrinol., February 1, 2007; 38(2): 221 - 233. [Abstract] [Full Text] [PDF]
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 N. Vasudevan and D. W. Pfaff Membrane-Initiated Actions of Estrogens in Neuroendocrinology: Emerging Principles Endocr. Rev., February 1, 2007; 28(1): 1 - 19. [Abstract] [Full Text] [PDF]
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 M. H. Al-Dhaheri and B. G. Rowan Protein Kinase A Exhibits Selective Modulation of Estradiol-Dependent Transcription in Breast Cancer Cells that Is Associated with Decreased Ligand Binding, Altered Estrogen Receptor {alpha} Promoter Interaction, and Changes in Receptor Phosphorylation Mol. Endocrinol., February 1, 2007; 21(2): 439 - 456. [Abstract] [Full Text] [PDF]
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 S. Massarweh and R. Schiff Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S15 - S24. [Abstract] [Full Text] [PDF]
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 K. Liang, Y. Lu, X. Li, X. Zeng, R. I. Glazer, G. B. Mills, and Z. Fan Differential Roles of Phosphoinositide-Dependent Protein Kinase-1 and Akt1 Expression and Phosphorylation in Breast Cancer Cell Resistance to Paclitaxel, Doxorubicin, and Gemcitabine Mol. Pharmacol., September 1, 2006; 70(3): 1045 - 1052. [Abstract] [Full Text] [PDF]
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P. R. Cutillas, A. Khwaja, M. Graupera, W. Pearce, S. Gharbi, M. Waterfield, and B. Vanhaesebroeck Ultrasensitive and absolute quantification of the phosphoinositide 3-kinase/Akt signal transduction pathway by mass spectrometry PNAS, June 13, 2006; 103(24): 8959 - 8964. [Abstract] [Full Text] [PDF]
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X. Li, Y. Lu, W. Jin, K. Liang, G. B. Mills, and Z. Fan Autophosphorylation of Akt at Threonine 72 and Serine 246: A POTENTIAL MECHANISM OF REGULATION OF Akt KINASE ACTIVITY J. Biol. Chem., May 12, 2006; 281(19): 13837 - 13843. [Abstract] [Full Text] [PDF]
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S. Glaros, N. Atanaskova, C. Zhao, D. F. Skafar, and K. B. Reddy Activation Function-1 Domain of Estrogen Receptor Regulates the Agonistic and Antagonistic Actions of Tamoxifen Mol. Endocrinol., May 1, 2006; 20(5): 996 - 1008. [Abstract] [Full Text] [PDF]
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A. Vilgelm, Z. Lian, H. Wang, S. L. Beauparlant, A. Klein-Szanto, L. H. Ellenson, and A. Di Cristofano Akt-Mediated Phosphorylation and Activation of Estrogen Receptor {alpha} Is Required for Endometrial Neoplastic Transformation in Pten+/- Mice. Cancer Res., April 1, 2006; 66(7): 3375 - 3380. [Abstract] [Full Text] [PDF]
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V. Vijayanathan, S. Venkiteswaran, S. K. Nair, A. Verma, T.J. Thomas, B. T. Zhu, and T. Thomas Physiologic levels of 2-methoxyestradiol interfere with nongenomic signaling of 17beta-estradiol in human breast cancer cells. Clin. Cancer Res., April 1, 2006; 12(7 Pt 1): 2038 - 2048. [Abstract] [Full Text] [PDF]
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N. Normanno, M. Di Maio, E. De Maio, A. De Luca, A. de Matteis, A. Giordano, F. Perrone, and on behalf of the NCI-Naples Breast Cancer Group Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer Endocr. Relat. Cancer, December 1, 2005; 12(4): 721 - 747. [Abstract] [Full Text] [PDF]
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S Zhang, X Li, R Burghardt, R Smith III, and S H Safe Role of estrogen receptor (ER) {alpha} in insulin-like growth factor (IGF)-I-induced responses in MCF-7 breast cancer cells J. Mol. Endocrinol., December 1, 2005; 35(3): 433 - 447. [Abstract] [Full Text] [PDF]
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S. Park, D. Kim, S. Kaneko, K. M. Szewczyk, S. V. Nicosia, H. Yu, R. Jove, and J. Q. Cheng Molecular Cloning and Characterization of the Human AKT1 Promoter Uncovers Its Up-regulation by the Src/Stat3 Pathway J. Biol. Chem., November 25, 2005; 280(47): 38932 - 38941. [Abstract] [Full Text] [PDF]
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T. Maffucci, E. Piccolo, A. Cumashi, M. Iezzi, A. M. Riley, A. Saiardi, H. Y. Godage, C. Rossi, M. Broggini, S. Iacobelli, et al. Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway by Inositol Pentakisphosphate Results in Antiangiogenic and Antitumor Effects Cancer Res., September 15, 2005; 65(18): 8339 - 8349. [Abstract] [Full Text] [PDF]
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C. Osipo, K. Meeke, H. Liu, D. Cheng, S. Lim, A. Weichel, and V. C. Jordan Trastuzumab Therapy for Tamoxifen-Stimulated Endometrial Cancer Cancer Res., September 15, 2005; 65(18): 8504 - 8513. [Abstract] [Full Text] [PDF]
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D. Bonofiglio, S. Gabriele, S. Aquila, S. Catalano, M. Gentile, E. Middea, F. Giordano, and S. Ando Estrogen Receptor {alpha} Binds to Peroxisome Proliferator-Activated Receptor Response Element and Negatively Interferes with Peroxisome Proliferator-Activated Receptor {gamma} Signaling in Breast Cancer Cells Clin. Cancer Res., September 1, 2005; 11(17): 6139 - 6147. [Abstract] [Full Text] [PDF]
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A. A. Kazi, J. M. Jones, and R. D. Koos Chromatin Immunoprecipitation Analysis of Gene Expression in the Rat Uterus in Vivo: Estrogen-Induced Recruitment of Both Estrogen Receptor {alpha} and Hypoxia-Inducible Factor 1 to the Vascular Endothelial Growth Factor Promoter Mol. Endocrinol., August 1, 2005; 19(8): 2006 - 2019. [Abstract] [Full Text] [PDF]
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G. J. Sabnis, D. Jelovac, B. Long, and A. Brodie The Role of Growth Factor Receptor Pathways in Human Breast Cancer Cells Adapted to Long-term Estrogen Deprivation Cancer Res., May 1, 2005; 65(9): 3903 - 3910. [Abstract] [Full Text] [PDF]
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W. Wollmann, M. L. Goodman, P. Bhat-Nakshatri, H. Kishimoto, R. J. Goulet Jr, S. Mehrotra, A. Morimiya, S. Badve, and H. Nakshatri The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells Carcinogenesis, May 1, 2005; 26(5): 900 - 907. [Abstract] [Full Text] [PDF]
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D. A. Levine, F. Bogomolniy, C. J. Yee, A. Lash, R. R. Barakat, P. I. Borgen, and J. Boyd Frequent Mutation of the PIK3CA Gene in Ovarian and Breast Cancers Clin. Cancer Res., April 15, 2005; 11(8): 2875 - 2878. [Abstract] [Full Text] [PDF]
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Y. M. Shah and B. G. Rowan The Src Kinase Pathway Promotes Tamoxifen Agonist Action in Ishikawa Endometrial Cells through Phosphorylation-Dependent Stabilization of Estrogen Receptor {alpha} Promoter Interaction and Elevated Steroid Receptor Coactivator 1 Activity Mol. Endocrinol., March 1, 2005; 19(3): 732 - 748. [Abstract] [Full Text] [PDF]
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 K. N. Felekkis, R. P. Narsimhan, R. Near, A. F. Castro, Y. Zheng, L. A. Quilliam, and A. Lerner AND-34 Activates Phosphatidylinositol 3-Kinase and Induces Anti-Estrogen Resistance in a SH2 and GDP Exchange Factor-Like Domain-Dependent Manner Mol. Cancer Res., January 1, 2005; 3(1): 32 - 41. [Abstract] [Full Text] [PDF]
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X. Cao, F. Kambe, L. C. Moeller, S. Refetoff, and H. Seo Thyroid Hormone Induces Rapid Activation of Akt/Protein Kinase B-Mammalian Target of Rapamycin-p70S6K Cascade through Phosphatidylinositol 3-Kinase in Human Fibroblasts Mol. Endocrinol., January 1, 2005; 19(1): 102 - 112. [Abstract] [Full Text] [PDF]
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A. Ring and M. Dowsett Mechanisms of tamoxifen resistance Endocr. Relat. Cancer, December 1, 2004; 11(4): 643 - 658. [Abstract] [Full Text] [PDF]
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M. H. Herynk and S. A. W. Fuqua Estrogen Receptor Mutations in Human Disease Endocr. Rev., December 1, 2004; 25(6): 869 - 898. [Abstract] [Full Text] [PDF]
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A.-M. Gaben, C. Saucier, M. Bedin, G. Redeuilh, and J. Mester Mitogenic Activity of Estrogens in Human Breast Cancer Cells Does Not Rely on Direct Induction of Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase or Phosphatidylinositol 3-Kinase Mol. Endocrinol., November 1, 2004; 18(11): 2700 - 2713. [Abstract] [Full Text] [PDF]
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 R. I. Fernando and J. Wimalasena Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt Mol. Biol. Cell, July 1, 2004; 15(7): 3266 - 3284. [Abstract] [Full Text] [PDF]
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F. Barletta, C.-W. Wong, C. McNally, B. S. Komm, B. Katzenellenbogen, and B. J. Cheskis Characterization of the Interactions of Estrogen Receptor and MNAR in the Activation of cSrc Mol. Endocrinol., May 1, 2004; 18(5): 1096 - 1108. [Abstract] [Full Text] [PDF]
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S. Baron, M. Manin, C. Beaudoin, L. Leotoing, Y. Communal, G. Veyssiere, and L. Morel Androgen Receptor Mediates Non-genomic Activation of Phosphatidylinositol 3-OH Kinase in Androgen-sensitive Epithelial Cells J. Biol. Chem., April 9, 2004; 279(15): 14579 - 14586. [Abstract] [Full Text] [PDF]
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 S. Aquila, D. Sisci, M. Gentile, E. Middea, S. Catalano, A. Carpino, V. Rago, and S. Ando Estrogen Receptor (ER){alpha} and ER{beta} Are Both Expressed in Human Ejaculated Spermatozoa: Evidence of Their Direct Interaction with Phosphatidylinositol-3-OH Kinase/Akt Pathway J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1443 - 1451. [Abstract] [Full Text] [PDF]
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W. Tangkeangsirisin, J. Hayashi, and G. Serrero PC Cell-Derived Growth Factor Mediates Tamoxifen Resistance and Promotes Tumor Growth of Human Breast Cancer Cells Cancer Res., March 1, 2004; 64(5): 1737 - 1743. [Abstract] [Full Text] [PDF]
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W. M. Cao, K. Murao, H. Imachi, X. Yu, H. Abe, A. Yamauchi, M. Niimi, A. Miyauchi, N. C. W. Wong, and T. Ishida A Mutant High-Density Lipoprotein Receptor Inhibits Proliferation of Human Breast Cancer Cells Cancer Res., February 15, 2004; 64(4): 1515 - 1521. [Abstract] [Full Text] [PDF]
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S. Mabuchi, M. Ohmichi, A. Kimura, Y. Nishio, E. Arimoto-Ishida, N. Yada-Hashimoto, K. Tasaka, and Y. Murata Estrogen Inhibits Paclitaxel-Induced Apoptosis via the Phosphorylation of Apoptosis Signal-Regulating Kinase 1 in Human Ovarian Cancer Cell Lines Endocrinology, January 1, 2004; 145(1): 49 - 58. [Abstract] [Full Text] [PDF]
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 H. Liu, E.-S. Lee, C. Gajdos, S. T. Pearce, B. Chen, C. Osipo, J. Loweth, K. McKian, A. De Los Reyes, L. Wing, et al. Apoptotic Action of 17{beta}-Estradiol in Raloxifene-Resistant MCF-7 Cells In Vitro and In Vivo J Natl Cancer Inst, November 5, 2003; 95(21): 1586 - 1597. [Abstract] [Full Text] [PDF]
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M. Sun, L. Yang, R. I. Feldman, X.-m. Sun, K. N. Bhalla, R. Jove, S. V. Nicosia, and J. Q. Cheng Activation of Phosphatidylinositol 3-Kinase/Akt Pathway by Androgen through Interaction of p85{alpha}, Androgen Receptor, and Src J. Biol. Chem., October 31, 2003; 278(44): 42992 - 43000. [Abstract] [Full Text] [PDF]
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 G. Zhang, B. He, and G. F. Weber Growth Factor Signaling Induces Metastasis Genes in Transformed Cells: Molecular Connection between Akt Kinase and Osteopontin in Breast Cancer Mol. Cell. Biol., September 15, 2003; 23(18): 6507 - 6519. [Abstract] [Full Text] [PDF]
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 G. Atalay, F. Cardoso, A. Awada, and M. J. Piccart Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer Ann. Onc., September 1, 2003; 14(9): 1346 - 1363. [Abstract] [Full Text] [PDF]
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L. A. deGraffenried, W. E. Friedrichs, L. Fulcher, G. Fernandes, J. M. Silva, J.-M. Peralba, and M. Hidalgo Eicosapentaenoic acid restores tamoxifen sensitivity in breast cancer cells with high Akt activity Ann. Onc., July 1, 2003; 14(7): 1051 - 1056. [Abstract] [Full Text] [PDF]
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M. Marino, F. Acconcia, and A. Trentalance Biphasic Estradiol-induced AKT Phosphorylation Is Modulated by PTEN via MAP Kinase in HepG2 Cells Mol. Biol. Cell, June 1, 2003; 14(6): 2583 - 2591. [Abstract] [Full Text] [PDF]
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 K. Liang, W. Jin, C. Knuefermann, M. Schmidt, G. B. Mills, K. K. Ang, L. Milas, and Z. Fan Targeting the Phosphatidylinositol 3-Kinase/Akt Pathway for Enhancing Breast Cancer Cells to Radiotherapy Mol. Cancer Ther., April 1, 2003; 2(4): 353 - 360. [Abstract] [Full Text] [PDF]
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H. Kurokawa and C. L. Arteaga ErbB (HER) Receptors Can Abrogate Antiestrogen Action in Human Breast Cancer by Multiple Signaling Mechanisms Clin. Cancer Res., January 1, 2003; 9(1): 511s - 515s. [Abstract] [Full Text]
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 K. J. Ho and J. K. Liao Nonnuclear Actions of Estrogen Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1952 - 1961. [Abstract] [Full Text] [PDF]
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 A. C. B. Cato, A. Nestl, and S. Mink Rapid Actions of Steroid Receptors in Cellular Signaling Pathways Sci. Signal., June 25, 2002; 2002(138): re9 - re9. [Abstract] [Full Text] [PDF]
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