Clinical Cancer Research Vol. 9, 511S-515s, January 2003
© 2003 American Association for Cancer Research
ErbB (HER) Receptors Can Abrogate Antiestrogen Action in Human Breast Cancer by Multiple Signaling Mechanisms1
Hirokazu Kurokawa and
Carlos L. Arteaga2
Departments of Medicine and Cancer Biology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6307
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ABSTRACT
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It has been reported that overexpression of the epidermal growth factor receptor (erbB1) or its homologous receptor, HER2 (erbB2), can confer antiestrogen resistance to estrogen receptor (ER)-positive human breast cancer cells. Aberrant signaling by receptors of the erbB network up-regulates a number of signaling pathways, which include phospholipase C-
1, Ras-Raf-mitogen-activated protein/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase, phosphatidylinositol 3'-kinase and its target, the serine/threonine kinase Akt, stress-activated protein kinases, signal transducers and activators of transcription, and c-Jun-NH2-terminal kinase (JNK). Akt has been reported to induce estrogen-independent transcription of ER. Here we show that transfection of ER-positive, HER2 gene-amplified BT-74 cells with an expression vector encoding dominant-negative (K179M) Akt1 partially restored the ability of tamoxifen to inhibit estradiol-stimulated ER reporter activity. Infection of MCF-7 cells with an adenovirus encoding myristoylated, constitutively active Akt induced ER reporter activity in the absence of estradiol and resulted in tamoxifen resistance of these cells in culture. Data will be presented to suggest that, in addition to mitogen-activated protein kinase, Akt is an important mediator of HER2-mediated antiestrogen resistance in human breast cancer cells.
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Introduction
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An unfortunate problem with all endocrine agents is that breast cancer cells usually become resistant to their action over time. Estrogen-dependent breast cancers typically progress from antiestrogen sensitive to being antiestrogen resistant. Several mechanisms have been proposed that contribute to the development of this resistant phenotype. These include the rare loss of ER3
by tumors, selection of ER mutations, alteration in the intracellular pharmacology and/or binding of antiestrogens to breast cancer cells, development of predominantly ligand-independent ER-mediated transcription, and perturbation of the interactions between ER and coactivators and corepressors of transcription (reviewed in Refs. 1
and 2
). Tamoxifen can repress or activate transcription of estrogen target genes. It has been shown with selective ER modulators like tamoxifen that the agonistic effects of these drugs can predominate upon the emergence of antiestrogen resistance, leading to breast tumor growth and/or secondary malignancies like uterine cancers (3)
.
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ErbB (HER) Tyrosine Kinases and Antiestrogen Resistance
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Several studies have suggested a causal association between overexpression and aberrant activity of the HER2/neu (erbB2) signaling pathway and antiestrogen resistance in human breast cancer (reviewed in Ref. 4
). The HER2 receptor is the protein product of the HER2 proto-oncogene and a member of the epidermal growth factor (EGFR, HER1) family of transmembrane receptor tyrosine kinases, which also includes HER3 and HER4. Upon binding of ligand to the EGFR, HER3 (erbB3), or HER4 (erbB4), HER2 is recruited as the preferred partner of these ligand-bound receptors into an active, phosphorylated heterodimeric complex that activates several signaling pathways involved in the proliferation and enhanced survival of tumor cells (5
, 6)
. This occurs by inducing receptor autophosphorylation in several COOH-terminal tyrosines and the recruitment of signal transducers and adaptor molecules that promote cellular proliferation, differentiation, motility, adhesion, protection from apoptosis, and cellular transformation (5
, 6)
. HER2 is capable of transforming normal mammary epithelial cells (7)
and is overexpressed in a cohort of women with breast tumors, where it is associated with more aggressive tumor behavior and poor patient prognosis (8)
. Patients with tumors that overexpress HER2 also exhibit statistically lower response rates and/or shorter duration of response to antiestrogen therapy (reviewed in Ref. 4
). The EGFR is another member of this receptor family, initially discovered as the proto-oncogene of the mutant, constitutively active oncogenic v-erbB tyrosine kinase that induced avian erythroblastosis (9)
. Unlike the mutant oncogene, the EGFR requires activation by binding of ligand to its extracellular domain, and its cellular effects depend on activation of its cytoplasmic tyrosine kinase. Overexpression of EGFR and its ligands is seen in several human cancers, and this is associated with increased tumor progression as well as antiestrogen resistance (reviewed in Ref. 10
). Taken together, these data suggest the EGFR/HER2 signaling network as a robust target in antiestrogen-resistant human breast cancer.
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Role of MAPK on HER2-induced Altered ER Transcription
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It has been shown that overexpression of HER2 in MCF-7 breast cancer cells results in MAPK hyperactivity and resistance to antiestrogens (11, 12, 13)
. In addition, MCF-7 cells grown in estrogen-depleted conditions exhibited increased MAPK activity; the activated MAPK made the cells more sensitive to estrogen, demonstrating the complex interplay between the ER and MAPK (14)
. MAPK hyperactivity promoted the increased association of the ER with coactivators and decreased association with corepressors, thus favoring hormone-dependent gene transcription (15
, 16)
. In that aberrant EGFR and HER2 signals can both hyperactivate MAPK, both receptors can lead to antiestrogen resistance by MAPK-dependent mechanisms. We recently reported data that strongly implicated enhanced MAPK signaling as the mediator of antiestrogen resistance in HER2-overexpressing tumor cells: (a) overexpression of ectopic HER2 in MCF-7 cells resulted in both activation of MAPK and tamoxifen resistance; (b) inhibition of MAPK with U0126 enhanced the ability of tamoxifen to inhibit both ER-mediated transcription and colony formation of MCF-7/HER2–18 and HER2-overexpressing BT-474 human breast cancer cells; (c) DN mutants of MEK1 and MEK2 also enhanced the inhibitory effect of tamoxifen on ER-mediated transcription; and (d) AG1478, an inhibitor of EGFR and HER2, markedly reduced active MAPK in MCF-7/HER2–18 xenografts, and this reduction was temporally associated with tamoxifen-induced growth restraint of tumors in vivo (12)
.
Activation of the Ras/MAPK signaling pathway has been shown to phosphorylate Ser-118 in ER
, resulting in ligand-independent receptor activation and/or loss of tamoxifen-induced inhibition of ER-mediated gene transcription (17
, 18)
. Therefore, we examined whether phosphorylation of Ser-118 was required for HER2-mediated tamoxifen resistance. For this purpose, we transfected WT ER, S118A ER, and S167A ER-luciferase constructs into ER-negative, HER2-overexpressing SKBR-3 breast cancer cells. In these cells, tamoxifen failed to inhibit 17ß-estradiol-induced WT ER reporter activity but completely inhibited hormone-induced S118A ER luciferase expression (Fig. 1)
, suggesting that phosphorylation at Ser-118 is required for HER2-mediated repression of tamoxifen action. Similar results were obtained with MDA-468 and MDA-231 ER-negative human breast cancer cells that overexpress EGFR (data not shown). Interestingly, tamoxifen partially inhibited the activity of the ER reporter construct with a mutation of the consensus Akt phosphorylation site Ser-167, also implicating Akt as an effector of HER2-induced blockade of tamoxifen action (discussed below).
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Fig. 1. Phosphorylation of ER in Ser-118 restores inhibitory effect of tamoxifen on ER-mediated transcription in HER2-overexpressing cells. ER-negative, HER2-amplified SKBR-3 breast cancer cells were transiently transfected with vectors encoding WT, S118A, and S167A ER [Ref. 38
; kindly provided by D. A. Lannigan (University of Virginia, Charlottesville, VA)] followed by a 20-h incubation with 1 nM 17ß-estradiol (E2; Sigma, St. Louis, MO) in the absence ( ) or presence ( ) of 1 µM 4-OH tamoxifen (Sigma) as described in Kurokawa et al. (12)
. Ethanol (0.1%) was used as control for 4-OH tamoxifen. Firefly luciferase activity and Renilla reniformis luciferase activity in SKBR-3 cell lysates were determined using the dual-luciferase reporter assay system (Promega, Madison, WI) according to the manufacturer’s instructions in a Monolight 2010 luminometer (Analytical Luminescence Laboratory, San Diego, CA). Firefly luciferase was normalized to R. reniformis luciferase activity and expressed as fold activation relative to wells not treated with estradiol. Each bar represents the mean relative luciferase activity from triplicate wells ± the SD.
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We next examined whether blocking HER2 and MAPK signaling would restore tamoxifen action in the ER-positive, HER2-amplified BT-474 breast cancer cells. For this purpose, we used: (a) ZD1839 (Iressa), a low molecular weight, ATP-competitive inhibitor of the EGFR tyrosine kinase (19)
that has recently been shown to potently inhibit HER2 phosphorylation in HER2-amplified cells (20, 21, 22)
; and (b) U0126, a noncompetitive inhibitor of the dual specificity MAPK kinases MEK1 and MEK2 (23)
, the enzymes that activate MAPK. ZD1839 or U0126 alone did not inhibit estradiol-stimulated estrogen response element-luciferase reporter activity in transiently transfected BT-474 cells. However, in a dose-dependent fashion, both agents unmasked the inhibitory effect of 4-OH tamoxifen on ER-mediated luciferase expression (Fig. 2)
. In addition, ZD1839 and U0126 markedly inhibited the levels of ER phosphorylated in Ser-118 as measured with a phospho-specific ER antibody (Fig. 2)
. Taken together, these data imply that: (a) MAPK plays a role in HER2-mediated antiestrogen resistance; (b) Ser-118 ER antibodies can be potentially used to prospectively identify breast tumors that are poised to resist tamoxifen action; and (c) exogenous inhibitors of HER2 and MAPK can be used therapeutically to restore and/or enhance the clinical response to antiestrogens.
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Fig. 2. A, blockade of HER2 and MAPKs unmasks inhibitory effect of tamoxifen on ER-mediated transcription. ER+, HER-amplified BT-474 human breast cancer cells were transiently transfected with pGLB-MERE (0.25 µg/well), an estrogen response element-containing luciferase reporter construct (provided by D. El-Ashry, University of Michigan, Ann Arbor, MI), in estrogen-free medium followed by a 16-h incubation with 1 nM 17ß-estradiol in the absence or presence of the indicated concentrations of ZD1839 (provided by S. Averbuch, AstraZeneca Pharmaceuticals, Wilmington, DE) or U0126 (Calbiochem, San Diego, CA). Fold activation of luciferase activity over estradiol-minus wells was expressed as described in the legend of Fig. 1
. Each bar represents the mean relative luciferase activity from triplicate wells ± the SD. B, ZD1839 and U0126 inhibit constitutive phosphorylation of BT-474 cell ER at Ser-118. BT-474 cells were treated overnight with 1 µM ZD1839 or 0.3 µM U0126. After washes in ice-cold PBS, cells were lysed in EBC buffer containing protease and phosphatase inhibitors as described previously (13)
, resolved by SDS-PAGE, transferred to nitrocellulose, and subjected to immunoblot analysis using a phospho-specific Ser-118 ER polyclonal antibody (kindly provided by C. Coombes, Imperial College of Science, Technology, and Medicine, Hammersmith Hospital, London, United Kingdom). Each lane contains 75 µg of total protein from whole cell lysates.
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PI3K/Akt Signaling and Antiestrogen Resistance
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Data shown in Fig. 1
suggest that phosphorylation of the Akt site Ser-167 is also involved in the ability of HER2 to abrogate tamoxifen action. These data are consistent with several reports that support an active interplay between PI3K and Akt signaling and the ER. For example, ER has been shown to bind the regulatory subunit of PI3K, p85, in ligand-dependent manner and activate PI3K and Akt (24
, 25)
. PI3K and Akt can mediate estradiol-induced S-phase entry and cyclin D1 transcription in MCF-7 cells (26)
. Furthermore, PI3K and Akt have been shown to induce phosphorylation of ER in Ser-167 and activate ER-mediated transcription (27)
. Finally, a constitutively active Akt mutant increases ER-mediated transcription and protects MCF-7 cells from tamoxifen-induced apoptosis (28)
. In this study, Ser-104, Ser-106, Ser-118, and Ser-167 appeared to play a role in the activation of ER by Akt. Infection of MCF-7 cells with an adenovirus encoding myristoylated (constitutively active) Akt (29)
induced ER reporter activity in the absence of estradiol and blocked the inhibitory effect of tamoxifen on estradiol-induced ER transcription.4
To examine the contribution of HER2-activated Akt to tamoxifen resistance, we tested the effect of a DN retrovirus encoding kinase-dead (K179M) Akt on ER reporter activity in BT-474 cells. As in Fig. 2
, tamoxifen failed to inhibit estradiol-induced ER reporter activity. However, infection with DN-Akt restored the inhibitory effect of 4-OH tamoxifen on ER-mediated luciferase expression (Fig. 3)
. A similar result was achieved by infection with a DN-MEK1 retrovirus. Interestingly, coinfection with both DN constructs enhanced the inhibitory effect of tamoxifen in supra-additive fashion (Fig. 3)
. One possible interpretation of these data is that both MAPK and Akt are involved in HER2-mediated abrogation of antiestrogen action. If so, we speculate that to block this effect of HER2, both pathways need to be effectively blocked to maximally restore antiestrogen action.
These results also suggest that ER-positive breast tumors with alterations of PI3K and Akt signaling (reviewed in Ref. 30
), independent of HER2, might also be less sensitive to antiestrogens. Several reports suggest that alterations in PI3K and Akt signaling are not uncommon among breast carcinomas. For example, Gershtein et al. (31)
reported increased levels of p85 protein and PI3K catalytic activity in paired breast tumor over adjacent nontumor tissue in 79% of examined specimens. Loss of PTEN, the 3-phosphoinositide-specific phosphatase, leads to derepression of Akt activity and cellular transformation (reviewed in Ref. 32
). Although mutations of PTEN occur in <5% of breast cancers (33)
, a recent report suggested the frequent loss of PTEN protein in breast cancers with hemizygous deletions of the Pten gene (34)
. Akt1 kinase activity is often increased in breast cancers with a poor prognosis (35)
, and Akt2 gene amplification has been reported in a cohort of women with breast tumors (36)
. Akt3 mRNA is up-regulated in ER-negative breast cancers (37)
, linking Akt3 with a more rapidly progressive, hormone-independent phenotype. Although the correlation of PI3K and Akt alterations with ER expression is unclear from the literature, the relative frequency of these alterations suggests the occurrence of hormone-dependent breast cancers in which PI3K and Akt will be set at a high threshold of activity. Based on the molecular biology studies summarized above and the data presented, we would anticipate that aberrant Akt signaling will block antiestrogen action and that those steroid receptor-positive cancers with high Akt signaling might be candidates for antiestrogens in combination with Akt inhibitors. These hypotheses will require further investigation.
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Open Discussion
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Dr. Kent Osborne: All of your preclinical data were with tamoxifen, and now, for the clinical trials, you’re switching to these other therapies. In our unpublished data looking at just WT MCF-7—not the HER2-overexpressing model—Iressa has no impact on estrogen withdrawal in terms of delaying resistance or any end point. It does delay resistance to tamoxifen in that situation, but the resistance developed to estrogen withdrawal or an aromatase inhibitor, if you want to make that extrapolation, is unaffected by Iressa. I think these studies should still be done. But if you want to use the models as a basis for the studies, you would not pick an aromatase inhibitor as the drug that you use, except in the HER2-overexpressing model.
Dr. Carlos L. Arteaga: We have picked an aromatase inhibitor because accrual to such a clinical trial would be easier. I would agree, though, that a key piece of preclinical data needed is whether HER2 confers resistance to aromatase inhibitors; that experiment has not been done yet, but I would bet HER2 overexpression will confer acquired resistance to aromatase inhibitors. The observations that estrogen-deprived cells acquire MAPK overexpression certainly suggest that acquired overexpression of EGFR and/or HER2 might not be unreasonable to expect in this setting of prolonged therapy with aromatase inhibitors. On the other hand, we have to realize that HER2 is a card-carrying oncogene and does not require the ER to transform a mammary cell. Therefore, the combination of an aromatase inhibitor and a HER2 inhibitor might still be supra-additive or synergistic, even though a mechanistic connection between both pathways may not be there.
Dr. Osborne: HER2 can stimulate growth, but we’re talking about using it to block resistance to hormone therapy, not to block its own intrinsic growth stimulatory properties. That’s a different issue.
Dr. Arteaga: I agree. I still think it can be a mechanism of escape from aromatase inhibitors that does not necessarily go through the ER.
Dr. Steven Come: How do you feel about the potential of fulvestrant combined with Iressa as opposed to the aromatase inhibitor with Iressa?
Dr. Osborne: Fulvestrant in our model works well, just like estrogen deprivation does in the HER2-overexpressing tumors. When they do develop resistance to fulvestrant, Iressa has an effect.
Dr. Come: In the findings Dr. Alan Wakeling presented last year at this meeting, fulvestrant looked a little bit better than tamoxifen, suggesting that fulvestrant was hopefully going to be a more effective way to block estrogen pathways and the next therapeutic increment could only be by targeting some second pathway, such as the EGF pathway. Then the aromatase inhibitor arm was proposed in Eastern Cooperative Oncology Group and we ended up with a trial of fulvestrant plus Iressa versus anastrozole plus Iressa.
Dr. Aman Buzdar: If the objective of that study is simply to determine safety using a fixed dose, it’s not necessary to enroll 80 patients per arm to get the safety data. Yes, you can give these two drugs together. Is it better to do so? No, you can’t show that. Why do you need 80 patients?
Dr. Arteaga: According to our statisticians, 68 patients are required to achieve our end points of safety and time to progression.
Dr. Eric Winer: We could just stop doing all Phase II trials ever.
Dr. Kathleen Pritchard: That’s also a very good idea.
Dr. Winer: We undoubtedly do too many Phase II trials, but this one is probably no worse than many Phase II trial designs.
Dr. Mitch Dowsett: There was never a Phase II trial done with Arimidex.
Dr. Arteaga: The randomized Phase II design of this trial was mandated by National Cancer Institute.
Dr. Dowsett: But it had been shown that estrogen suppression would go through the floor with Arimidex, and this would provide clinical effectiveness.
Dr. Arteaga: Precisely. Here we don’t have that. We don’t know the cohort that will benefit.
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FOOTNOTES
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1 Presented at the Second International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer, June 28–29, 2002, Cambridge, MA. Supported in part by NIH Grant R01 CA80195 (to C. L. A.) and Vanderbilt-Ingram Comprehensive Cancer Center NCI Support Grant CA68485. 
2 To whom correspondence should be addressed, at Division of Oncology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 777 PRB, Nashville, TN 37232-6307. Phone: (615) 936-3524 or -1919; Fax: (615) 936-1790; E-mail: carlos.arteaga{at}vanderbilt.edu
3 The abbreviations used are: ER, estrogen receptor; EGFR, epidermal growth factor receptor; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3'-kinase; DN, dominant-negative; MEK, mitogen-activated protein/extracellular signal-regulated kinase kinase; WT, wild-type.
4 C. L. Arteaga, unpublished data.
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Top
ABSTRACT
Introduction
