© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 24, 1852-1857,
December 19, 2001
© 2001 Oxford University Press
REPORT |
Insulin-Like Growth Factor-I Receptor Signaling and Resistance to Trastuzumab (Herceptin)
Affiliations of authors: Y. Lu, X. Zi, Y. Zhao, M. Pollak, Department of Oncology, Jewish General Hospital, and McGill University, Montreal, PQ, Canada; D. Mascarenhas, Protigen Incorporated, Mountain View, CA.
Correspondence to: Michael Pollak, M.D., Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, PQ, Canada H3T 1E2 (e-mail: michael.pollak{at}mcgill.ca).
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ABSTRACT |
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Background: Trastuzumab (Herceptin), an anti-HER2/neu receptor monoclonal antibody that inhibits growth of ErbB2-overexpressing breast cancer, is used to treat such cancers. Development of resistance to trastuzumab, however, is common. We investigated whether insulin-like growth factor-I (IGF-I), which activates cell survival signals, interferes with the growth-inhibitory action of trastuzumab. Methods: MCF-7/HER2-18 and SKBR3 human breast cancer models were used to assess cell proliferation, colony formation in soft agar, and cell cycle parameters. Throughout, we used trastuzumab at a dose of 10 µg/mL and IGF-I at a dose of 40 ng/mL. All statistical tests were two-sided. Results: Trastuzumab inhibited the growth of MCF-7/HER2-18 cells, which overexpress HER2/neu receptors and express IGF-I receptors (IGF-IRs), only when IGF-IR signaling was minimized. For example, in 1% fetal bovine serum (FBS), trastuzumab reduced cell proliferation by 42% (P = .002); however, in 10% FBS or IGF-I, trastuzumab had no effect on proliferation. In SKBR3 cells, which overexpress HER2/neu receptor but express few IGF-IRs, trastuzumab reduced proliferation by 42% (P = .008) regardless of IGF-I concentration. When SKBR3 cells were genetically altered to overexpress IGF-IRs and cultured with IGF-I, trastuzumab had no effect on proliferation. However, the addition of IGF-binding protein-3, which decreased IGF-IR signaling, restored trastuzumab-induced growth inhibition. Conclusions: In breast cancer cell models that overexpress HER2/neu, an increased level of IGF-IR signaling appears to interfere with the action of trastuzumab. Thus, strategies that target IGF-IR signaling may prevent or delay development of resistance to trastuzumab.
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INTRODUCTION |
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The HER2/neu (ErbB2) proto-oncogene encodes a 185-kd transmembrane receptor protein with intrinsic tyrosine kinase activity. No soluble ErbB2 ligand has been identified, but ligand binding to the other members of the ErbB family induces receptor heterodimerization and activation of ErbB2 (1–5). Overexpression of ErbB2 was hypothesized to be associated with an aggressive phenotype, and this association was observed in clinical correlative studies (6,7).
Many methods have been used to therapeutically target HER2 in HER2-overexpressing cancers (8,9), including the use of anti-HER2/neu antibodies (10,11). Preclinical studies (11–13) demonstrated the antiproliferative activity of the murine 4D5 antibody and a humanized version of 4D5, named trastuzumab (Herceptin; Genentech, San Francisco, CA), against HER2/neu-overexpressing breast cancers. Clinical trials (14–17) have shown that trastuzumab has important activity against HER2-positive metastatic breast cancer.
Trastuzumab is often cited as a prototype for rationally designed antineoplastic drugs that target critical signal transduction pathways (8,17,18). However, not all HER2-overexpressing cancer cells respond to treatment with 4D5 or trastuzumab (19), and the clinical benefit of the drug is limited by the fact that most cancers become resistant to trastuzumab therapy in less than 12 months (16,17). The mechanisms of resistance to trastuzumab are poorly understood.
The association between insulin-like growth factor (IGF) physiology and neoplasia is supported by epidemiologic evidence that higher levels of circulating IGF-I are associated with increased risk of several cancers (20–26) and laboratory evidence that IGF signaling pathways are perturbed in neoplastic cells (27–29). IGF-I receptor (IGF-IR) activation stimulates signaling pathways involved in mitogenesis and cell survival (30,31). Therefore, we examined the possibility that IGF-IR signaling interferes with the antiproliferative actions of trastuzumab.
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MATERIALS AND METHODS |
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Cell Culture and Transfection
SKBR3 human breast cancer cells (from the American Type Culture Collection, Manassas, VA) and MCF-7/HER2-18 cells (32) (provided by Dr. M. Alaoui-Jamali, McGill University, Montreal, PQ, Canada) were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) at 37 °C and 5% CO2 and 95% air.
A 4.7-kilobase, full-length human IGF-IR complementary DNA was obtained from the PECE/IGF-IR plasmid (33) by EcoRI digestion and was inserted into the pcDNA3.1(+) expression vector (Invitrogen Inc., Carlsbad, CA). SKBR3 cells stably transfected with pcDNA3.1(+)/IGF-IR were generated by calcium phosphate transfection and selected after 3 weeks in G418 at 800 µg/mL (Life Technologies, Inc. [GIBCO BRL], Burlington, ON, Canada).
Cell Proliferation Assay
We used a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay after confirming high correlation of this end point with a cell number end point in preliminary work. We plated 105cells in six-well plates in medium containing 10% FBS. After 24 hours, the medium was changed to test medium specific for each experiment. After 72 hours, the MTT assay was done in triplicate: MTT (Sigma Chemical Co., St. Louis, MO) was added to a final concentration of 1 mg/mL, the reaction mixture was incubated for 3 hours at 37 °C, and the absorbance was measured at 570 nm. The 95% confidence interval (CI) never exceeded 81% to 119% of the mean for each observation. Trastuzumab was purchased from the Oncology Pharmacy of the Jewish General Hospital, Montreal, and was used at 10 µg/mL unless otherwise specified; recombinant human IGF-binding protein-3 (IGFBP-3) and IGF-I were from Protigen Incorporated, Mountain View, CA, and were used at 1 µg/mL and 40 ng/mL, respectively, unless otherwise specified. 
-IR3, a blocking antibody against the IGF-IR, was from Oncogene Research Products (Boston, MA).
Soft-Agar Assay
Anchorage-independent cell growth was measured in six-well plates. A 1-mL layer of 0.8% agar (Sigma Chemical Co.) in tissue culture medium was solidified in the bottom of each well. Cells to be assayed were suspended at 37 °C in 1 mL of 0.35% agar in tissue culture medium, and then 3 x 103 MCF-7/HER2-18 cells, 5 x 103 SKBR3 cells, or 5 x 103 SKBR3/IGF-IR cells were added per well. Trastuzumab, IGF-I, and IGFBP-3 were then added in 2 mL of medium to the top of the agar, and the medium was changed every 3 days. After about 25 days, all of the colonies were counted under a dissection microscope. Colonies were defined as clusters of 30 or more cells. The 95% CI never exceeded 76% to 124% of the mean for each observation.
Flow Cytometry
The cells were plated in 100-mm dishes at 30% confluence. After 24 hours, the medium was changed to the test medium. After 72 hours, the cells were washed twice with ice-cold phosphate-buffered saline (PBS) and fixed in 70% ethanol at –20 °C overnight. The cells were washed twice with ice-cold PBS and resuspended in propidium iodide buffer (i.e., PBS [pH 7.4], 0.1% Triton X-100, 0.1 mM EDTA, ribonuclease A [0.05 mg/mL], and propidium iodide [50 µg/mL]). After 30 minutes at room temperature, the cell cycle distribution was determined by flow cytometry with a FACScan (Beckman-Coulter, Fullerton, CA). Duplicate experiments yielded similar results.
Western Blots
After each treatment, the cells were lysed in RIPA buffer (0.1 mM dibasic sodium phosphate, 1.7 mM monobasic sodium phosphate, 150 mM NaCl, 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate [SDS], 0.2 mM sodium vanadate, 0.2 mM phenylmethylsulfonyl fluoride, and aprotinin at 0.2 U/mL). Protein from clarified lysates (20–60 µg) was resolved electrophoretically on denaturing SDS–polyacrylamide gels (8%–12%), transferred to nitrocellulose membranes, and probed with the following primary antibodies: anti-Cdk2 (where Cdk is cyclin-dependent kinase), anti-Cdk6, anti-cyclin E, and anti-IGF-IR
from Santa Cruz Biotechnology (Santa Cruz, CA) and anti-p21Cip1, anti-Cdk4, and anti-p27Kip1 from Neomarkers, Inc. (Fremont, CA). The position of proteins was visualized with horseradish peroxidase-conjugated anti-mouse or anti-rabbit antibodies.
Immunoprecipitation
To assess the effects of IGF-I and recombinant human IGFBP-3 on IGF-IR activation in SKBR3 and SKBR3/IGF-IR cells, we washed cultures that were 70%–80% confluent twice and then added serum-free medium for 24 hours. Fifteen minutes before harvesting, the cultures were treated with saline vehicle, IGFBP-3 at 1 µg/mL, and/or IGF-I at 40 ng/mL at 37 °C. Monolayers were quickly washed twice with ice-cold PBS and lysed with 0.4 mL of lysis buffer (i.e., 10 mM Tris–HCl [pH 7.4], 150 mM NaCl, 1% Triton X-100, 1 mM EDTA, 1 mM EGTA [i.e., ethyleneglycolbis(aminoethyl)-N,N,N`,N`-tetraacetic acid], 0.2 mM sodium vanadate, 0.2 mM phenylmethylsulfonyl fluoride, 0.5% Nonidet P-40, and aprotinin at 0.2 U/mL). Phosphotyrosine levels in IGF-IR were measured in protein extracts (300 µg) by use of anti-IGF-IR and a specific anti-phosphotyrosine antibody (Upstate Biotechnology, Lake Placid, NY).
For Cdk2-p27Kip1 and Cdk2-p21Cip1 coimmunoprecipitation experiments, clarified protein lysates (200 µg/mL) were precleared with 25 µL of protein A–Sepharose (Santa Cruz Biotechnology) and precipitated with 2 µg of anti-Cdk2 antibody (Santa Cruz Biotechnology) and 25 µL of protein A–Sepharose overnight at 4 °C; Cdk2-p27Kip1 and Cdk2-p21Cip1 complexes were detected by immunoblotting.
Statistical Analysis
All of the data are shown as means and 95% CIs, unless otherwise specified. To assess the statistical significance of observed differences, we used Student's t test. All statistical tests were two-sided, and P values less than .05 were considered to be statistically significant.
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RESULTS |
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TopNotesAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effects of IGF-I and Trastuzumab on MCF-7/HER2-18 Cells
MCF-7/HER2-18 cells are MCF-7 human breast cancer cells that overexpress HER2/neu (32). We confirmed the observation (32) that the growth of neither MCF-7 nor MCF-7/HER2-18 cells in 10% FBS is inhibited by trastuzumab (data not shown). The growth of MCF-7/HER2-18 cells, however, was inhibited by trastuzumab when the FBS concentration was reduced (Fig. 1, A
), suggesting that a component of FBS blocks the antiproliferative effect of trastuzumab. IGF-I (40 ng/mL) reduced trastuzumab-induced growth inhibition to the same extent as 10% FBS (Fig. 1, B).
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MCF-7 cells express IGF-IRs, and their growth is inhibited by the anti-IGF-IR antibody
-IR3 or the IGF-binding protein IGFBP-3, both of which interfere with ligand–receptor interactions (34,35). MCF-7/HER2-18 cells were responsive to IGF-I, and the modest trastuzumab-induced growth inhibition observed with 5% FBS was enhanced by -IR3 or IGFBP-3 (Fig. 1, C
). In 5% FBS, trastuzumab inhibited proliferation to 83% of control (P = .04), whereas trastuzumab plus -IR3 at 0.5 µg/mL or trastuzumab plus IGFBP-3 at 1 µg/mL inhibited proliferation to 50% and 47% of control, respectively (P<.001 in each case). Dose–response data for IGFBP-3 effects on proliferation singly and in combination with trastuzumab are shown in Fig. 1, D. When anchorage-independent MCF-7/HER2-18 cell growth was assayed in soft agar with 10% FBS, trastuzumab alone did not inhibit colony formation, IGFBP-3 (1 µg/mL) alone reduced colony formation by 29%, and the combination reduced colony formation by 82%, which was statistically significantly greater (P<.001) than growth inhibition with either agent alone (data not shown). Overexpression of IGF-IR and Trastuzumab-Induced Growth Inhibition of SKBR3 Cells
SKBR3 human breast cancer cells overexpress HER2/neu but have less than 10% the number of IGF-IRs in MCF-7/HER2-18 cells. The IGF-IR-transfected SKBR3 clone SKBR3/IGF-IR has about sevenfold more IGF-IRs than MCF-7/HER2-18 cells. Mock-transfected SKBR3/neo cells and SKBR3 cells have approximately the same number of IGF-IRs, as estimated by densitometric scanning of western blots (data not shown).
In contrast to the findings with MCF-7/HER2-18 cells, trastuzumab inhibits SKBR3/neo cell proliferation in the presence or absence of FBS (11). Maximal trastuzumab-induced growth inhibition of SKBR3/neo cells was 42% (Fig. 2, A). The proliferation rate of SKBR3/IGF-IR cells was 125% that of SKBR3/neo cells, and trastuzumab reduced their proliferation by only 20% (Fig. 2, A). In soft-agar assays (Fig. 2, B), trastuzumab reduced SKBR3 colony formation by 62%, but it reduced SKBR3/IGF-IR colony formation by only 12% (Fig. 2, B). Trastuzumab was a statistically significantly better inhibitor of SKBR3/neo cells than of SKBR3/IGF-IR cells under both anchored (P = .02) and anchorage-independent (P = .004) conditions.
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In the presence of IGF-I, SKBR3/neo cells but not SKBR3/IGF-IR cells were growth inhibited by trastuzumab. Trastuzumab statistically significantly reduced (P = .004) the proliferation of SKBR3/neo cells but did not affect (P = .92) the proliferation of SKBR3/IGF-IR cells (Fig. 2, C
). Addition of IGFBP-3 restored or even enhanced the trastuzumab-induced growth inhibition of SKBR3/IGF-IR cells in the presence of IGF-I (Fig. 2, C). In SKBR3/IGF-IR cells cultured with IGF-I and trastuzumab, where trastuzumab had no growth-inhibitory effect on cell proliferation, immunoprecipitation experiments detected the highest level of IGF-IR phosphorylation (i.e., activation); addition of IGFBP-3 to these cultures reduced IGF-IR phosphorylation by 75% (data not shown). Overexpression of IGF-IR and Trastuzumab-Induced G1-Phase Arrest
An increased proportion of cells in G1 phase is associated with the reduced rate of cell proliferation induced by trastuzumab or antibody 4D5 (19,36). Flow cytometry revealed that trastuzumab increased the percentage of SKBR3/IGF-IR cells and SKBR3/neo cells in G1 phase, but the increase was less in SKBR3/IGF-IR cells (Fig. 2, D). In SKBR3/IGF-IR cells, this increase was blocked completely by IGF-I and restored by IGFBP-3.
Modification of Downstream Effects of Trastuzumab by IGF-I
Anti-HER2/neu antibodies induce the Cdk inhibitor p27Kip1, which associates with Cdk2 and contributes to growth inhibition (36). By using western blots, we investigated the effect of IGF-IR signaling on Cdk inhibitors. Baseline levels of p27Kip1 and p21Cip1 were substantially lower in SKBR3/IGF-IR cells than in SKBR3/neo cells. Trastuzumab induced p27Kip1 expression in SKBR3/neo cells but not in SKBR3/IGF-IR cells. An increased amount of Cdk2-associated p27Kip1 was observed in trastuzumab-treated SKBR3/neo cells but not in trastuzumab-treated SKBR3/IGF-IR cells (data not shown).
Early- and mid-G1 cyclins were reported previously to be inhibited by anti-HER2 antibodies (36). We observed that cyclin E levels were higher in SKBR3/IGF-IR cells than in SKBR3/neo control cells. Although trastuzumab reduced cyclin E levels in both lines, the reduction was greater in SKBR3/neo cells. IGF-I reversed this reduction in SKBR3/IGF-IR cells (data not shown).
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DISCUSSION |
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The common occurrence of clinical resistance to trastuzumab suggests either that many molecular alterations can confer such resistance or that a few mechanisms conferring such resistance arise frequently. In the latter case, there would be a particularly strong rationale for determining whether targeting both HER2/neu and a pathway commonly implicated in resistance would be clinically beneficial. Our results suggest that molecular alterations resulting in enhanced activation of IGF-IR and/or pathways distal to IGF-IR represent one family of mechanisms of resistance to trastuzumab.
Specific molecular lesions that might confer such resistance to trastuzumab include overexpression of IGF-I or IGF-II, underexpression of growth-inhibitory IGFBPs, overexpression of IGFBP proteases, or reduced activity of intracellular phosphatases, such as PTEN, that normally limit IGF-I signaling. Although these alterations have been described in breast cancer, it has not been possible to observe sequential changes in gene expression as trastuzumab-sensitive cancers become resistant to trastuzumab, because women are not generally subjected to repeat biopsy after trastuzumab resistance has been observed clinically.
IGF-IR signaling has not been reported previously to confer resistance to trastuzumab-induced growth inhibition. This mechanism is plausible, however, because IGF-I and trastuzumab affect downstream events, such as cyclin E expression, in opposite directions (9,36–38). Given recent insights into signaling networks (39–45), it is likely that IGF-I and trastuzumab perturb these networks in opposite directions, rather than acting independently on two linear signaling pathways that intersect at one node.
Our results suggest that targeting several signal transduction pathways simultaneously may lead to more effective control of neoplastic growth than targeting a single pathway and add to the evidence (25–29) that the IGF-IR pathway is an attractive target. However, we urge the establishment of banks of sequential tumor biopsy specimens to determine if changes in signal transduction networks (particularly IGF-IR signaling) associated with the development of resistance to trastuzumab or to other drugs in patients correlate with findings in laboratory models.
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NOTES |
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Editor's note: Representatives of Protigen Incorporated reviewed and approved this report. D. Mascarenhas is the chief executive officer of Protigen Incorporated, which supplied the insulin-like growth factor-binding protein-3 for this research.
Supported by grants from the "Streams of Excellence" Program of the Canadian Breast Cancer Initiative, from the National Cancer Institute of Canada, and from the Canadian Institutes for Health Research.
We thank colleagues in the Canadian Breast Cancer Research Initiative Streams of Excellence Program for useful discussions of this work.
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REFERENCES |
|---|
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TopNotesAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1 Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–37.[CrossRef][Web of Science][Medline]
2 Wada T, Qian XL, Greene MI. Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell 1990;61:1339–47.[CrossRef][Web of Science][Medline]
3 Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, et al. ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 1996;15:254–64.[Web of Science][Medline]
4 Beerli RR, Graus-Porta D, Woods-Cook K, Chen X, Yarden Y, Hynes NE. Neu differentiation factor activation of ErbB-3 and ErbB-4 is cell specific and displays a differential requirement for ErbB-2. Mol Cell Biol 1995;15:6496–505.[Abstract]
5 Graus-Porta D, Beerli RR, Hynes NE. Single-chain antibody-mediated intracellular retention of ErbB-2 impairs Neu differentiation factor and epidermal growth factor signaling. Mol Cell Biol 1995;15:1182–91.[Abstract]
6
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707–12.
7
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–82.
8 Bange J, Zwick E, Ullrich A. Molecular targets for breast cancer therapy and prevention. Nat Med 2001;7:548–52.[CrossRef][Web of Science][Medline]
9 Yu D, Hung MC. Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 2000;19:6115–21.[CrossRef][Web of Science][Medline]
10 Baselga J, Mendelsohn J. Receptor blockade with monoclonal antibodies as anti-cancer therapy. Pharmacol Ther 1994;64:127–54.[CrossRef][Web of Science][Medline]
11
Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 1989;9:1165–72.
12
Baselga J, Norton L, Albanell J, Kim YM, Mendelsohn J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 1998;58:2825–31.
13 Pietras RJ, Pegram MD, Finn RS, Maneval DA, Slamon DJ. Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 1998;17:2235–49.[CrossRef][Web of Science][Medline]
14
Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996;14:737–44.
15 Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998;16:2659–71.[Abstract]
16 Baselga J. Clinical trials of Herceptin (trastuzumab). Eur J Cancer 2001;37 Suppl 1:18–24.
17
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–92.
18
Eisenhauer EA. From the molecule to the clinic—inhibiting HER2 to treat breast cancer [editorial]. N Engl J Med 2001;344:841–2.
19
Lane HA, Beuvink I, Motoyama AB, Daly JM, Neve RM, Hynes NE. ErbB2 potentiates breast tumor proliferation through modulation of p27(Kip1)–Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol Cell Biol 2000;20:3210–23.
20
Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:563–6.
21 Holly JM. Insulin-like growth factor-I and new opportunities for cancer prevention. Lancet 1998;351:1373–5.[CrossRef][Web of Science][Medline]
22
Smith GD, Gunnell D, Holly J. Cancer and insulin-like growth factor-I. A potential mechanism linking the environment with cancer risk [editorial]. BMJ 2000;321:847–8.
23 Pollak M. Insulin-like growth factor physiology and cancer risk. Eur J Cancer 2000;36:1224–8.
24 Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 1998;351:1393–6 [see also editorial comments Lancet 1998;351:1373–5].[CrossRef][Web of Science][Medline]
25
Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 2000;92:1472–89.
26
Pollak M. Insulin-like growth factors and prostate cancer. Epidemiol Rev 2001;23:59–66.
27 Resnicoff M, Baserga R. The role of the insulin-like growth factor I receptor in transformation and apoptosis. Ann N Y Acad Sci 1998;842:76–81.[CrossRef][Web of Science][Medline]
28
Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 2000;21:215–44.
29
Nickerson T, Chang F, Lorimer D, Smeekens SP, Sawyers CL, Pollak M. In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgen independence is associated with increased expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR). Cancer Res 2001;61:6276–80.
30 O'Connor R, Fennelly C, Krause D. Regulation of survival signals from the insulin-like growth factor-I receptor. Biochem Soc Trans 2000;28:47–51.[Web of Science][Medline]
31
LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 1995;16:143–63.
32 Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, et al. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 1993;24:85–95.
33
Gustafson TA, Rutter WJ. The cysteine-rich domains of the insulin and insulin-like growth factor I receptors are primary determinants of hormone binding specificity. Evidence from receptor chimeras. J Biol Chem 1990;265:18663–7.
34 Nickerson T, Huynh H, Pollak M. Insulin-like growth factor binding protein-3 induces apoptosis in MCF7 breast cancer cells [published erratum appears in Biochem Biophys Res Commun 1997;240:246]. Biochem Biophys Res Commun 1997;237:690–3.[CrossRef][Web of Science][Medline]
35
Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev 1999;20:761–87.
36
Le XF, McWatters A, Wiener J, Wu JY, Mills GB, Bast RC Jr. Anti-HER2 antibody and heregulin suppress growth of HER2-overexpressing human breast cancer cells through different mechanisms. Clin Cancer Res 2000;6:260–70.
37
Lai A, Sarcevic B, Prall OW, Sutherland RL. Insulin/insulin-like growth factor-I and estrogen cooperate to stimulate cyclin E-Cdk2 activation and cell cycle progression in MCF-7 breast cancer cells through differential regulation of cyclin E and p21WAF1/Cip1. J Biol Chem 2001;276:25823–33.
38
Dupont J, Karas M, LeRoith D. The potentiation of estrogen on insulin-like growth factor I action in MCF-7 human breast cancer cells includes cell cycle components. J Biol Chem 2000;275:35893–901.
39 Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001;411:342–8.[CrossRef][Medline]
40 Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001;411:355–65.[CrossRef][Medline]
41 Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature 2001;410:37–40.[CrossRef][Medline]
42 Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211–25.[CrossRef][Web of Science][Medline]
43 Fambrough D, McClure K, Kazlauskas A, Lander ES. Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes. Cell 1999;97:727–41.[CrossRef][Web of Science][Medline]
44 Gschwind A, Zwick E, Prenzel N, Leserer M, Ullrich A. Cell communication networks: epidermal growth factor receptor transactivation as the paradigm for interreceptor signal transmission. Oncogene 2001;20:1594–600.[CrossRef][Web of Science][Medline]
45 Jordan JD, Landau EM, Lyengar R. Signaling networks: the origins of cellular multitasking. Cell 2000;103:193–200.[CrossRef][Web of Science][Medline]
Manuscript received June 15, 2001; revised October 5, 2001; accepted October 31, 2001.
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 J. S. Ross, E. A. Slodkowska, W. F. Symmans, L. Pusztai, P. M. Ravdin, and G. N. Hortobagyi The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti-HER-2 Therapy and Personalized Medicine Oncologist, April 1, 2009; 14(4): 320 - 368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Law, G. Habibi, K. Hu, H. Masoudi, M. Y.C. Wang, A. L. Stratford, E. Park, J. M.W. Gee, P. Finlay, H. E. Jones, et al. Phosphorylated Insulin-Like Growth Factor-I/Insulin Receptor Is Present in All Breast Cancer Subtypes and Is Related to Poor Survival Cancer Res., December 15, 2008; 68(24): 10238 - 10246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J.A. Eichhorn, M. Gili, M. Scaltriti, V. Serra, M. Guzman, W. Nijkamp, R. L. Beijersbergen, V. Valero, J. Seoane, R. Bernards, et al. Phosphatidylinositol 3-Kinase Hyperactivation Results in Lapatinib Resistance that Is Reversed by the mTOR/Phosphatidylinositol 3-Kinase Inhibitor NVP-BEZ235 Cancer Res., November 15, 2008; 68(22): 9221 - 9230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Lewis Phillips, G. Li, D. L. Dugger, L. M. Crocker, K. L. Parsons, E. Mai, W. A. Blattler, J. M. Lambert, R. V.J. Chari, R. J. Lutz, et al. Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate Cancer Res., November 15, 2008; 68(22): 9280 - 9290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Chen, Y. Wang, S. E Kane, and S. Chen Improvement of sensitivity to tamoxifen in estrogen receptor-positive and Herceptin-resistant breast cancer cells J. Mol. Endocrinol., November 1, 2008; 41(5): 367 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Esparis-Ogando, A. Ocana, R. Rodriguez-Barrueco, L. Ferreira, J. Borges, and A. Pandiella Synergic antitumoral effect of an IGF-IR inhibitor and trastuzumab on HER2-overexpressing breast cancer cells Ann. Onc., November 1, 2008; 19(11): 1860 - 1869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Buck, A. Eyzaguirre, M. Rosenfeld-Franklin, S. Thomson, M. Mulvihill, S. Barr, E. Brown, M. O'Connor, Y. Yao, J. Pachter, et al. Feedback Mechanisms Promote Cooperativity for Small Molecule Inhibitors of Epidermal and Insulin-Like Growth Factor Receptors Cancer Res., October 15, 2008; 68(20): 8322 - 8332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. P. Hu, S. B. Patil, M. Panasiewicz, W. Li, J. Hauser, L. E. Humphrey, and M. G. Brattain Heterogeneity of Receptor Function in Colon Carcinoma Cells Determined by Cross-talk between Type I Insulin-like Growth Factor Receptor and Epidermal Growth Factor Receptor Cancer Res., October 1, 2008; 68(19): 8004 - 8013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Martin, A. Miller, L. Emad, M. Rahmani, T. Walker, C. Mitchell, M. P. Hagan, M. A. Park, A. Yacoub, P. B. Fisher, et al. Lapatinib Resistance in HCT116 Cells Is Mediated by Elevated MCL-1 Expression and Decreased BAK Activation and Not by ERBB Receptor Kinase Mutation Mol. Pharmacol., September 1, 2008; 74(3): 807 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bianco, R. Rosa, V. Damiano, G. Daniele, T. Gelardi, S. Garofalo, V. Tarallo, S. De Falco, D. Melisi, R. Benelli, et al. Vascular Endothelial Growth Factor Receptor-1 Contributes to Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Cancer Cells Clin. Cancer Res., August 15, 2008; 14(16): 5069 - 5080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Rowe, T. Ozbay, L. M. Bender, and R. Nahta Nordihydroguaiaretic acid, a cytotoxic insulin-like growth factor-I receptor/HER2 inhibitor in trastuzumab-resistant breast cancer Mol. Cancer Ther., July 1, 2008; 7(7): 1900 - 1908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Piao, Y. Wang, Y. Adachi, H. Yamamoto, R. Li, A. Imsumran, H. Li, T. Maehata, M. Ii, Y. Arimura, et al. Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas Mol. Cancer Ther., June 1, 2008; 7(6): 1483 - 1493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Matsubara, Y. Yamada, Y. Hirashima, D. Takahari, N. T. Okita, K. Kato, T. Hamaguchi, K. Shirao, Y. Shimada, and T. Shimoda Impact of Insulin-Like Growth Factor Type 1 Receptor, Epidermal Growth Factor Receptor, and HER2 Expressions on Outcomes of Patients with Gastric Cancer Clin. Cancer Res., May 15, 2008; 14(10): 3022 - 3029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Portera, J. M. Walshe, D. R. Rosing, N. Denduluri, A. W. Berman, U. Vatas, M. Velarde, C. K. Chow, S. M. Steinberg, D. Nguyen, et al. Cardiac Toxicity and Efficacy of Trastuzumab Combined with Pertuzumab in Patients with Trastuzumab-Insensitive Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Clin. Cancer Res., May 1, 2008; 14(9): 2710 - 2716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. C. Carver and L. A. Schuler Prolactin Does Not Require Insulin-Like Growth Factor Intermediates but Synergizes with Insulin-Like Growth Factor I in Human Breast Cancer Cells Mol. Cancer Res., April 1, 2008; 6(4): 634 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Shattuck, J. K. Miller, K. L. Carraway III, and C. Sweeney Met Receptor Contributes to Trastuzumab Resistance of Her2-Overexpressing Breast Cancer Cells Cancer Res., March 1, 2008; 68(5): 1471 - 1477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Chakraborty, K. Liang, and M. P. DiGiovanna Co-Targeting Insulin-Like Growth Factor I Receptor and HER2: Dramatic Effects of HER2 Inhibitors on Nonoverexpressing Breast Cancer Cancer Res., March 1, 2008; 68(5): 1538 - 1545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Johnston, M. Trudeau, B. Kaufman, H. Boussen, K. Blackwell, P. LoRusso, D. P. Lombardi, S. Ben Ahmed, D. L. Citrin, M. L. DeSilvio, et al. Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy J. Clin. Oncol., March 1, 2008; 26(7): 1066 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Oh, Q. Jin, E. S. Kim, F. R. Khuri, and H.-Y. Lee Insulin-like Growth Factor-I Receptor Signaling Pathway Induces Resistance to the Apoptotic Activities of SCH66336 (Lonafarnib) through Akt/Mammalian Target of Rapamycin-Mediated Increases in Survivin Expression Clin. Cancer Res., March 1, 2008; 14(5): 1581 - 1589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ocana and A. Pandiella Identifying Breast Cancer Druggable Oncogenic Alterations: Lessons Learned and Future Targeted Options Clin. Cancer Res., February 15, 2008; 14(4): 961 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Aird, X. Ding, A. Baras, J. Wei, M. A. Morse, T. Clay, H. K. Lyerly, and G. R. Devi Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression Mol. Cancer Ther., January 1, 2008; 7(1): 38 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sapino, F. Montemurro, C. Marchio, G. Viale, J. Kulka, M. Donadio, A. Bottini, G. Botti, A. P. dei Tos, A. Bersiga, et al. Patients with advanced stage breast carcinoma immunoreactive to biotinylated Herceptin(R) are most likely to benefit from trastuzumab-based therapy: an hypothesis-generating study Ann. Onc., December 1, 2007; 18(12): 1963 - 1968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Ellis and R. Crowder "PIKing" the Winner for Phosphatidylinositol 3-Kinase Inhibitors in ErbB2-Positive Breast Cancer: Let's Not "PTENed" It's Easy! Clin. Cancer Res., October 1, 2007; 13(19): 5661 - 5662. [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Lu, S. L. Wyszomierski, L.-M. Tseng, M.-H. Sun, K.-H. Lan, C. L. Neal, G. B. Mills, G. N. Hortobagyi, F. J. Esteva, and D. Yu Preclinical Testing of Clinically Applicable Strategies for Overcoming Trastuzumab Resistance Caused by PTEN Deficiency Clin. Cancer Res., October 1, 2007; 13(19): 5883 - 5888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. K. Rowinsky, H. Youssoufian, J. R. Tonra, P. Solomon, D. Burtrum, and D. L. Ludwig IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor Clin. Cancer Res., September 15, 2007; 13(18): 5549s - 5555s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kumar ErbB-Dependent Signaling as a Determinant of Trastuzumab Resistance Clin. Cancer Res., August 15, 2007; 13(16): 4657 - 4659. [Full Text] [PDF]
|
|
|
|
|
|
C. A. Ritter, M. Perez-Torres, C. Rinehart, M. Guix, T. Dugger, J. A. Engelman, and C. L. Arteaga Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor Network Clin. Cancer Res., August 15, 2007; 13(16): 4909 - 4919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G Valabrega, F Montemurro, and M Aglietta Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer Ann. Onc., June 1, 2007; 18(6): 977 - 984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Scaltriti, F. Rojo, A. Ocana, J. Anido, M. Guzman, J. Cortes, S. Di Cosimo, X. Matias-Guiu, S. Ramon y Cajal, J. Arribas, et al. Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast Cancer J Natl Cancer Inst, April 18, 2007; 99(8): 628 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Shattuck, J. K. Miller, M. Laederich, M. Funes, H. Petersen, K. L. Carraway III, and C. Sweeney LRIG1 Is a Novel Negative Regulator of the Met Receptor and Opposes Met and Her2 Synergy Mol. Cell. Biol., March 1, 2007; 27(5): 1934 - 1946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. N.C. Chiu, L. A. Edwards, A. I. Kapanen, M. M. Malinen, W. H. Dragowska, C. Warburton, G. G. Chikh, K. Y.Y. Fang, S. Tan, J. Sy, et al. Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs Mol. Cancer Ther., March 1, 2007; 6(3): 844 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Arteaga Will Single-Time Tumor Profiling and a "Guilt by Association" Approach Allow Us to Outsmart HER2-Positive Breast Cancer? Clin. Cancer Res., February 15, 2007; 13(4): 1071 - 1073. [Full Text] [PDF]
|
|
|
|
|
|
L. N. Harris, F. You, S. J. Schnitt, A. Witkiewicz, X. Lu, D. Sgroi, P. D. Ryan, S. E. Come, H. J. Burstein, B.-A. Lesnikoski, et al. Predictors of Resistance to Preoperative Trastuzumab and Vinorelbine for HER2-Positive Early Breast Cancer Clin. Cancer Res., February 15, 2007; 13(4): 1198 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Manara, L. Landuzzi, P. Nanni, G. Nicoletti, D. Zambelli, P. L. Lollini, C. Nanni, F. Hofmann, C. Garcia-Echeverria, P. Picci, et al. Preclinical In vivo Study of New Insulin-Like Growth Factor-I Receptor-Specific Inhibitor in Ewing's Sarcoma Clin. Cancer Res., February 15, 2007; 13(4): 1322 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nahta, L. X.H. Yuan, Y. Du, and F. J. Esteva Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling Mol. Cancer Ther., February 1, 2007; 6(2): 667 - 674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E Jones, J. M W Gee, I. R Hutcheson, J. M Knowlden, D. Barrow, and R. I Nicholson Growth factor receptor interplay and resistance in cancer Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S45 - S51. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. R Hutcheson, J. M Knowlden, H. E Jones, R. S Burmi, R. A McClelland, D. Barrow, J. M W Gee, and R. I Nicholson Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S89 - S97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Meric-Bernstam and M.-C. Hung Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin. Cancer Res., November 1, 2006; 12(21): 6326 - 6330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-H. Tseng, Y.-C. Wang, S.-C. Weng, J.-R. Weng, C.-S. Chen, R. W. Brueggemeier, C. L. Shapiro, C.-Y. Chen, S. E. Dunn, M. Pollak, et al. Overcoming Trastuzumab Resistance in HER2-Overexpressing Breast Cancer Cells by Using a Novel Celecoxib-Derived Phosphoinositide-Dependent Kinase-1 Inhibitor Mol. Pharmacol., November 1, 2006; 70(5): 1534 - 1541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Massarweh, C. K. Osborne, S. Jiang, A. E. Wakeling, M. Rimawi, S. K. Mohsin, S. Hilsenbeck, and R. Schiff 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., August 15, 2006; 66(16): 8266 - 8273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wang, G. Chakravarty, S. Kim, Y. D. Yazici, M. N. Younes, S. A. Jasser, A. A. Santillan, C. D. Bucana, A. K. El-Naggar, and J. N. Myers Growth-Inhibitory Effects of Human Anti-Insulin-Like Growth Factor-I Receptor Antibody (A12) in an Orthotopic Nude Mouse Model of Anaplastic Thyroid Carcinoma Clin. Cancer Res., August 1, 2006; 12(15): 4755 - 4765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Jerome, N. Alami, S. Belanger, V. Page, Q. Yu, J. Paterson, L. Shiry, M. Pegram, and B. Leyland-Jones Recombinant Human Insulin-like Growth Factor Binding Protein 3 Inhibits Growth of Human Epidermal Growth Factor Receptor-2-Overexpressing Breast Tumors and Potentiates Herceptin Activity In vivo. Cancer Res., July 15, 2006; 66(14): 7245 - 7252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. E. Kim and G. Serrero PC Cell-Derived Growth Factor Stimulates Proliferation and Confers Trastuzumab Resistance to Her-2-Overexpressing Breast Cancer Cells. Clin. Cancer Res., July 15, 2006; 12(14): 4192 - 4199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Swanton, A. Futreal, and T. Eisen Her2-targeted therapies in non-small cell lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4377s - 4383s. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Xia, S. Bacus, P. Hegde, I. Husain, J. Strum, L. Liu, G. Paulazzo, L. Lyass, P. Trusk, J. Hill, et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer PNAS, May 16, 2006; 103(20): 7795 - 7800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nahta, L. X.H. Yuan, B. Zhang, R. Kobayashi, and F. J. Esteva Insulin-like Growth Factor-I Receptor/Human Epidermal Growth Factor Receptor 2 Heterodimerization Contributes to Trastuzumab Resistance of Breast Cancer Cells Cancer Res., December 1, 2005; 65(23): 11118 - 11128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Menendez, L. Vellon, R. Colomer, and R. Lupu Effect of {gamma}-Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene J Natl Cancer Inst, November 2, 2005; 97(21): 1611 - 1615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
P. Bali, M. Pranpat, R. Swaby, W. Fiskus, H. Yamaguchi, M. Balasis, K. Rocha, H.-G. Wang, V. Richon, and K. Bhalla Activity of Suberoylanilide Hydroxamic Acid Against Human Breast Cancer Cells with Amplification of Her-2 Clin. Cancer Res., September 1, 2005; 11(17): 6382 - 6389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, J. Hailey, D. Williams, Y. Wang, P. Lipari, M. Malkowski, X. Wang, L. Xie, G. Li, D. Saha, et al. Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody Mol. Cancer Ther., August 1, 2005; 4(8): 1214 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Menendez, L. Vellon, and R. Lupu Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene Ann. Onc., August 1, 2005; 16(8): 1253 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Altundag, O. Altundag, P. Morandi, B. Ozcakar, C. Boruban, M. Tanner, and J. Isola The role of insulin-like growth factor-I receptor in the development of Herceptin resistance Mol. Cancer Ther., July 1, 2005; 4(7): 1136 - 1136. [Full Text] [PDF]
|
|
|
|
|
|
H E Jones, J M W Gee, K M Taylor, D Barrow, H D Williams, M Rubini, and R I Nicholson Development of strategies for the use of anti-growth factor treatments Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S173 - S182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Lu, H. Zhang, H. Koo, J. Tonra, P. Balderes, M. Prewett, E. Corcoran, V. Mangalampalli, R. Bassi, D. Anselma, et al. A Fully Human Recombinant IgG-like Bispecific Antibody to Both the Epidermal Growth Factor Receptor and the Insulin-like Growth Factor Receptor for Enhanced Antitumor Activity J. Biol. Chem., May 20, 2005; 280(20): 19665 - 19672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. L. Spector, W. Xia, H. Burris III, H. Hurwitz, E. C. Dees, A. Dowlati, B. O'Neil, B. Overmoyer, P. K. Marcom, K. L. Blackwell, et al. Study of the Biologic Effects of Lapatinib, a Reversible Inhibitor of ErbB1 and ErbB2 Tyrosine Kinases, on Tumor Growth and Survival Pathways in Patients With Advanced Malignancies J. Clin. Oncol., April 10, 2005; 23(11): 2502 - 2512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Baselga and C. L. Arteaga Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer J. Clin. Oncol., April 10, 2005; 23(11): 2445 - 2459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Criswell, M. Beman, S. Araki, K. Leskov, E. Cataldo, L. D. Mayo, and D. A. Boothman Delayed Activation of Insulin-like Growth Factor-1 Receptor/Src/MAPK/Egr-1 Signaling Regulates Clusterin Expression, a Pro-survival Factor J. Biol. Chem., April 8, 2005; 280(14): 14212 - 14221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Menendez, L. Vellon, R. Colomer, and R. Lupu Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (HerceptinTM) in breast cancer cells with Her-2/neu oncogene amplification Ann. Onc., March 1, 2005; 16(3): 359 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tuccillo, M. Romano, T. Troiani, E. Martinelli, F. Morgillo, F. De Vita, R. Bianco, G. Fontanini, R. A. Bianco, G. Tortora, et al. Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor-2 and Epidermal Growth Factor Receptor Small Molecule Tyrosine Kinase Inhibitor, in Combination with SC-236, a Cyclooxygenase-2 Inhibitor Clin. Cancer Res., February 1, 2005; 11(3): 1268 - 1276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Nagy, E. Friedlander, M. Tanner, A. I. Kapanen, K. L. Carraway, J. Isola, and T. M. Jovin Decreased Accessibility and Lack of Activation of ErbB2 in JIMT-1, a Herceptin-Resistant, MUC4-Expressing Breast Cancer Cell Line Cancer Res., January 15, 2005; 65(2): 473 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Camp, J. Summy, T. W. Bauer, W. Liu, G. E. Gallick, and L. M. Ellis Molecular Mechanisms of Resistance to Therapies Targeting the Epidermal Growth Factor Receptor Clin. Cancer Res., January 1, 2005; 11(1): 397 - 405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H E Jones, L Goddard, J M W Gee, S Hiscox, M Rubini, D Barrow, J M Knowlden, S Williams, A E Wakeling, and R I Nicholson Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells Endocr. Relat. Cancer, December 1, 2004; 11(4): 793 - 814. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Nagle, Z. Ma, M. A. Byrne, M. F. White, and L. M. Shaw Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis Mol. Cell. Biol., November 15, 2004; 24(22): 9726 - 9735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. Dang, A. J. Dannenberg, K. Subbaramaiah, M. N. Dickler, M. M. Moasser, A. D. Seidman, G. M. D'Andrea, M. Theodoulou, K. S. Panageas, L. Norton, et al. Phase II Study of Celecoxib and Trastuzumab in Metastatic Breast Cancer Patients Who Have Progressed after Prior Trastuzumab-Based Treatments Clin. Cancer Res., June 15, 2004; 10(12): 4062 - 4067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Rabindran, C. M. Discafani, E. C. Rosfjord, M. Baxter, M. B. Floyd, J. Golas, W. A. Hallett, B. D. Johnson, R. Nilakantan, E. Overbeek, et al. Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase Cancer Res., June 1, 2004; 64(11): 3958 - 3965. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Warburton, W. H. Dragowska, K. Gelmon, S. Chia, H. Yan, D. Masin, T. Denyssevych, A. E. Wallis, and M. B. Bally Treatment of HER-2/neu Overexpressing Breast Cancer Xenograft Models with Trastuzumab (Herceptin) and Gefitinib (ZD1839): Drug Combination Effects on Tumor Growth, HER-2/neu and Epidermal Growth Factor Receptor Expression, and Viable Hypoxic Cell Fraction Clin. Cancer Res., April 1, 2004; 10(7): 2512 - 2524. [Abstract] [Full Text] [PDF]
|
|
|
|
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M. Klinger, H. Farhan, H. Just, H. Drobny, G. Himmler, H. Loibner, G. C. Mudde, M. Freissmuth, and V. Sexl Antibodies Directed against Lewis-Y Antigen Inhibit Signaling of Lewis-Y Modified ErbB Receptors Cancer Res., February 1, 2004; 64(3): 1087 - 1093. [Abstract] [Full Text] [PDF]
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D. Lu, H. Zhang, D. Ludwig, A. Persaud, X. Jimenez, D. Burtrum, P. Balderes, M. Liu, P. Bohlen, L. Witte, et al. Simultaneous Blockade of Both the Epidermal Growth Factor Receptor and the Insulin-like Growth Factor Receptor Signaling Pathways in Cancer Cells with a Fully Human Recombinant Bispecific Antibody J. Biol. Chem., January 23, 2004; 279(4): 2856 - 2865. [Abstract] [Full Text] [PDF]
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F. Ciardiello, R. Bianco, R. Caputo, R. Caputo, V. Damiano, T. Troiani, D. Melisi, F. De Vita, S. De Placido, A. R. Bianco, et al. Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Human Cancer Cells with Acquired Resistance to Antiepidermal Growth Factor Receptor Therapy Clin. Cancer Res., January 15, 2004; 10(2): 784 - 793. [Abstract] [Full Text] [PDF]
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T. O. Nielsen, H. N. Andrews, M. Cheang, J. E. Kucab, F. D. Hsu, J. Ragaz, C. B. Gilks, N. Makretsov, C. D. Bajdik, C. Brookes, et al. Expression of the Insulin-Like Growth Factor I Receptor and Urokinase Plasminogen Activator in Breast Cancer Is Associated with Poor Survival: Potential for Intervention with 17-Allylamino Geldanamycin Cancer Res., January 1, 2004; 64(1): 286 - 291. [Abstract] [Full Text] [PDF]
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R. I. Nicholson, I. R. Hutcheson, J. M. Knowlden, H. E. Jones, M. E. Harper, N. Jordan, S. E. Hiscox, D. Barrow, and J. M. W. Gee Nonendocrine Pathways and Endocrine Resistance: Observations with Antiestrogens and Signal Transduction Inhibitors in Combination Clin. Cancer Res., January 1, 2004; 10(1): 346S - 354S. [Abstract] [Full Text] [PDF]
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X. Cui and A. V. Lee Regulatory Nodes That Integrate and Coordinate Signaling as Potential Targets for Breast Cancer Therapy Clin. Cancer Res., January 1, 2004; 10(1): 396S - 401S. [Abstract] [Full Text] [PDF]
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D. Burtrum, Z. Zhu, D. Lu, D. M. Anderson, M. Prewett, D. S. Pereira, R. Bassi, R. Abdullah, A. T. Hooper, H. Koo, et al. A Fully Human Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor Blocks Ligand-Dependent Signaling and Inhibits Human Tumor Growth in Vivo Cancer Res., December 15, 2003; 63(24): 8912 - 8921. [Abstract] [Full Text] [PDF]
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 D. B. Boyd Insulin and Cancer Integr Cancer Ther, December 1, 2003; 2(4): 315 - 329. [Abstract] [PDF]
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L. Fuino, P. Bali, S. Wittmann, S. Donapaty, F. Guo, H. Yamaguchi, H.-G. Wang, P. Atadja, and K. Bhalla Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B Mol. Cancer Ther., October 1, 2003; 2(10): 971 - 984. [Abstract] [Full Text] [PDF]
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H. Lapillonne, M. Konopleva, T. Tsao, D. Gold, T. McQueen, R. L. Sutherland, T. Madden, and M. Andreeff Activation of Peroxisome Proliferator-activated Receptor {gamma} by a Novel Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid Induces Growth Arrest and Apoptosis in Breast Cancer Cells Cancer Res., September 15, 2003; 63(18): 5926 - 5939. [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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E. K. Maloney, J. L. McLaughlin, N. E. Dagdigian, L. M. Garrett, K. M. Connors, X.-M. Zhou, W. A. Blattler, T. Chittenden, and R. Singh An Anti-Insulin-like Growth Factor I Receptor Antibody That Is a Potent Inhibitor of Cancer Cell Proliferation Cancer Res., August 15, 2003; 63(16): 5073 - 5083. [Abstract] [Full Text] [PDF]
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M. P. Goetz, D. O. Toft, M. M. Ames, and C. Erlichman The Hsp90 chaperone complex as a novel target for cancer therapy Ann. Onc., August 1, 2003; 14(8): 1169 - 1176. [Abstract] [Full Text] [PDF]
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D. H. Johnson and C. L. Arteaga Gefitinib in Recurrent Non-Small-Cell Lung Cancer: An IDEAL Trial? J. Clin. Oncol., June 15, 2003; 21(12): 2227 - 2229. [Full Text] [PDF]
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C. L. Arteaga and J. Baselga Clinical Trial Design and End Points for Epidermal Growth Factor Receptor-targeted Therapies: Implications for Drug Development and Practice Clin. Cancer Res., May 1, 2003; 9(5): 1579 - 1589. [Full Text] [PDF]
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D. Sachdev, S.-L. Li, J. S. Hartell, Y. Fujita-Yamaguchi, J. S. Miller, and D. Yee A Chimeric Humanized Single-Chain Antibody against the Type I Insulin-like Growth Factor (IGF) Receptor Renders Breast Cancer Cells Refractory to the Mitogenic Effects of IGF-I Cancer Res., February 1, 2003; 63(3): 627 - 635. [Abstract] [Full Text] [PDF]
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R. Nahta, G. N. Hortobagyi, and F. J. Esteva Growth Factor Receptors in Breast Cancer: Potential for Therapeutic Intervention Oncologist, February 1, 2003; 8(1): 5 - 17. [Abstract] [Full Text] [PDF]
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A. Hurbin, L. Dubrez, J.-L. Coll, and M.-C. Favrot Inhibition of Apoptosis by Amphiregulin via an Insulin-like Growth Factor-1 Receptor-dependent Pathway in Non-small Cell Lung Cancer Cell Lines J. Biol. Chem., December 13, 2002; 277(51): 49127 - 49133. [Abstract] [Full Text] [PDF]
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J. Albanell and J. Baselga Unraveling Resistance to Trastuzumab (Herceptin): Insulin-Like Growth Factor-I Receptor, a New Suspect J Natl Cancer Inst, December 19, 2001; 93(24): 1830 - 1832. [Full Text] [PDF]
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