Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors
- Caroline Rousseau†1, 2,
- Anne Lise Ruellan†2,
- Karine Bernardeau2,
- Françoise Kraeber-Bodéré1, 2, 3,
- Sebastien Gouard2,
- Delphine Loussouarn4,
- Catherine Saï-Maurel2,
- Alain Faivre-Chauvet2,
- John Wijdenes5,
- Jacques Barbet2,
- Joëlle Gaschet2,
- Michel Chérel1, 2 and
- François Davodeau2Email author
© Rousseau et al; licensee Springer. 2011
Received: 19 April 2011
Accepted: 1 September 2011
Published: 1 September 2011
Overexpression of syndecan-1 (CD138) in breast carcinoma correlates with a poor prognosis and an aggressive phenotype. The objective of this study was to evaluate the potential of targeting CD138 by immuno-PET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either 124I or 131I in nude mice engrafted with the triple-negative MDA-MB-468 breast cancer cell line.
The immunoreactivity of 125I-B-B4 (80%) was determined, and the affinity of 125I-B-B4 and the expression of CD138 on MDA-MB-468 was measured in vitro by Scatchard analysis. CD138 expression on established tumors was confirmed by immunohistochemistry. A biodistribution study was performed in mice with subcutaneous MDA-MB-468 and 125I-B-B4 at 4, 24, 48, 72, and 96 h after injection and compared with an isotype-matched control. Tumor uptake of B-B4 was evaluated in vivo by immuno-PET imaging using the 124I-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with 131I-B-B4 and the RIT efficacy evaluated.
125I-B-B4 affinity was in the nanomolar range (Kd = 4.39 ± 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 × 104 ± 9.27 × 102 epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of 125I-B-B4 peaked at 14% injected dose (ID) per gram at 24 h and was higher than that of the isotype-matched control mAb (5% ID per gram at 24 h). Immuno-PET performed with 124I-B-B4 on tumor-bearing mice confirmed the specificity of B-B4 uptake and its retention within the tumor. The MTD was reached at 22.2 MBq. All mice treated with RIT (n = 8) as a single treatment at the MTD experienced a partial (n = 3) or complete (n = 5) response, with three of them remaining tumor-free 95 days after treatment.
These results demonstrate that RIT with 131I-B-B4 could be considered for the treatment of metastatic triple-negative breast cancer that cannot benefit from hormone therapy or anti-Her2/neu immunotherapy. Immuno-PET for visualizing CD138-expressing tumors with 124I-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging.
Keywordsbreast cancer syndecan-1 CD138 radioimmunotherapy immuno-PET monoclonal antibody
The expression of syndecan-1 in breast cancer is described as a poor prognostic factor. However, the potential of targeting this antigen for immuno-PET or radioimmunotherapy has not yet been investigated. Syndecans represent a four-member family of transmembrane cell-surface heparan sulfate proteoglycans. Their biological effects on adhesion, migration, and growth factor signaling are thought to be mediated by their binding to growth factors, including FGFs, VEGF, HGF, or ECM molecules, via their HS chains [1–3]. Syndecan-1, also named CD138, is expressed by normal epithelial cells but is also transiently expressed in condensing mesenchyma during embryonic morphogenesis . The biological functions of syndecan-1 potentially affect several steps in tumor progression and facilitate metastasis . A prognostic value has been assigned to changes in syndecan-1 expression in several cancer types, including breast, colorectal, gastric, pancreatic, prostate, lung, endometrial, and ovarian cancers, as well as squamous cell carcinoma of the head and neck and multiple myeloma [6, 7]. Syndecan-1 appears particularly interesting for breast carcinoma radioimmunotherapy (RIT). The antigen is expressed by potentially aggressive breast carcinomas, and its expression is tightly associated with the absence of estrogen receptors (ER) as well as with a high Ki67 proliferation index . Triple-negative (ER-negative, progesterone receptor (PR)-negative, HER2/neu not overexpressed) breast cancer (TNBC) represents approximately 15% of all breast carcinomas . It generally occurs in women below the age of 50 years and is associated with a high risk of distant recurrence and death during the first 3 to 5 years of follow-up . Cytotoxic chemotherapy is currently the only treatment available for TNBC patients, but most of them have chemoresistant rampant disease with a poor prognosis. However, novel targeted therapies have the potential to change its natural course . Monoclonal antibody therapy is one such targeted therapy that may prove beneficial in the management of these breast cancer subtypes [9, 12].
B-B4 is a murine IgG1 mAb targeting syndecan-1 that was originally developed for multiple myeloma by Wijdenes and colleagues . The B-B4 mAb has been shown to have high specificity for syndecan-1, but it is not cytotoxic for myeloma cells . Subsequently, one study reported that 131I-labeled B-B4 mAb induced cellular death in an in vitro multiple myeloma model .
Several radioimmunotherapy clinical trials have been performed for breast cancer treatment targeting Tag 72, mucin, CEA, and an adenocarcinoma antigen recognized by the ChL6 antibody [16–19]. However, objective tumor responses were obtained with limited toxicity compared to standard chemotherapy treatment of patients at the same disease stage. Repeated dosing with radiolabeled antibody or combination of RIT with other therapeutic agents might further improve RIT efficacy.
To date, there has been no study investigating the diagnostic and therapeutic potential of radiolabeled B-B4 mAb in breast carcinoma, particularly in TNBC cells such as the MDA-MB-468 cell line that shows many of the recurrent basal-like molecular abnormalities . The aim of this study was thus to evaluate the biodistribution, toxicity, and RIT efficacy of the radioiodinated anti-CD138 antibody B-B4 in mice xenografted with the MDA-MB-468 TNBC cell line.
The human TNBC cell line MDA-MB-468 was obtained from LGC Promochem (Molsheim, France). The MDA-MB-468 cell line was cultured in adherent-cell monolayers in RPMI medium (Gibco BRL, Cergy-Pontoise, France) supplemented with 10% bovine calf serum (Gibco BRL), 1% glutamine (L-glutamine 200 mM; Gibco BRL), and 1% antibiotic (penicillin 100 U/ml, streptomycin 100 U/ml; Gibco BRL). The human myeloma cell line U266 used for the radiolabeled B-B4 immunoreactivity assay was obtained from the American Type Culture collection (Rockville, MD, USA).
NMRI-nu (nu/nu) mice over 8 to 10 weeks of age were grafted subcutaneously in the right flank with 5 × 106 MDA-MB-468 cells in 0.1 mL of PBS. The animals were housed in aseptic conditions. Lugol's 1% solution was added to drinking water (0.1 mL/L) 2 days before RIT and then 2 weeks after injecting the radioiodinated reagent. The mice were injected with radiolabeled mAb 24 days after MDA-MB-468 engraftment once the tumor volume had reached a mean volume of 108 ± 55 mm3. The mice were housed in our animal core facility according to ongoing national regulations issued by INSERM and the French Department of Agriculture. The experiments performed in this study were approved by the local veterinary services (license number B44.565).
Antibodies and radiolabeling
The reference antibody was the B-B4 anti-CD138 mAb (IgG1). This mouse IgG1 was kindly provided by Diaclone (Besançon, France). The 7D4 mAb was used as the isotype-matched control in the biodistribution studies . This mAb recognizes the CMH-peptide complex formed by peptide MAGE3 271-279 and HLA-A2. This epitope is not expressed on MDA-MB-468 cells. The antibodies were labeled with 125I (PerkinElmer 16, Avenue du Québec, Courtaboeuf Cedex 1, France) using the iodogen method . The 125I-labeled mAb was purified on a PD10 column. The B-B4 mAb was also labeled with 131I (MDS Nordion, Zoning Industriel, Avenue de L'Espérance, Fleurus, Belgium) using the same iodogen method. The specific activity ranged from 185 to 200 MBq/mg. Radiolabeling efficiency estimated by instant thin-layer chromatography (ITLC) was above 95%. The 131I-labeled antibody was not purified further. Iodine-124 (IBA molecular, Chemin du cyclotron, 3, Louvain-la-Neuve, Belgium)
labeling of the B-B4 mAb for immuno-PET imaging was performed according to a previously described method . Briefly, 1.7 mg (350 μL) B-B4 in 0.1 M phosphate buffer pH 7 and 20 μl (0.1 mg) of iodogen in DMF were added to a glass vial containing 230 μL (222 MBq) of Na124I. After 15 min of incubation under gentle mixing at room temperature, the radiolabeled antibody was purified by gel filtration on NAPTM-5 columns (GE Healthcare UK, Little Chalfont Buckinghamshire, UK). The 124I-B-B4 was recovered in 1.15 ml. The specific activity was 90 mBq/mg, and the radiochemical purity of the purified radiolabeled antibody was greater than 98% as determined by ITLC-SG chromatography using trichloroacetic acid at 10% w/v in distilled water as a mobile phase.
Immunoreactivity and affinity
The immunoreactivity of radiolabeled B-B4 was determined according to the "Lindmo" cell-binding assay using CD138-positive U266 cells . The number of antigen-binding sites per MDA-MB-468 cells was determined by Scatchard analysis as previously described . The binding data were subjected to nonlinear regression analysis using a one-site equilibrium binding equation with Prism software.
Tumor sections (4 μm) were cut from the tissue microarray blocks and placed on superfrost slides. The immunochemical technique was performed with an automated immuno-stainer (Labvision, Fremont, CA, USA) using the strepatavidin-biotin amplification technique (ChemMate kit, Dako, Glostrup, Denmark) after appropriate antigen retrieval in EDTA buffer (pH 8) at 95°C. This involved the application of a specific primary antibody to syndecan-1/CD138 (clone MI15, 1:100, Dako). A secondary anti-mouse antibody conjugated to peroxidase was used for revelation. Peroxidase activity was revealed using 3,3'-diamino-benzidine for 5 min. Sections were counterstained with Harris hematoxylin for 3 min. Negative controls were obtained by omitting primary antibodies.
MDA-MB-468 tumor-bearing mice were given 4 MBq of 125I-labeled B-B4 (5 μg) via the tail vein. The mice were killed 4, 24, 48, 72, and 96 h after injection (three mice per time point), the tumor and organs were removed, weighed, and the radioactivity counted using a gamma counter. The results were expressed as percent ID per gram. The same protocol was applied for biodistribution of the control isotype-matched 7D4 mAb.
Immuno-PET imaging with 124I-labeled B-B4 was performed on six NMRI-nu (nu/nu) mice bearing MDA-MB-468 xenografts. An activity of 3.3 MBq of 124I-labeled B-B4 (90 μg) was injected intravenously, and PET images were acquired 1, 2, 3, 4, and 8 days after injection, with an Inveon PET scanner (Siemens Medical Solutions, Knoxville, TN, USA) under anesthesia (isoflurane-O2). A CT scan was performed using the docked CT module (Siemens Medical Solutions, Knoxville, TN, USA).
PET imaging with 18FDG was performed on three NMRI-nu (nu/nu) mice bearing MDA-MB-468 xenografts receiving an intravenous injection of 6.2 MBq of 18FDG. PET images were acquired 1 h after injection. PET data were collected over a period of 20 min (one bed position), and the 3D sinograms were reconstructed using a 3D ordered subset expectation maximization followed by a maximum a posteriori algorithm (3D OSEM-MAP).
Dose escalation and toxicity of 131I-labeled B-B4
The mice were injected i.v. in the lateral tail vein with escalating activity of 131I-labeled B-B4 mAb. The amount of B-B4 mAb was adjusted to 120 μg by adding unlabeled B-B4 antibody and the injected doses were adjusted to a constant volume of 0.2 ml with sterile PBS. These groups received 0.0 MBq (n = 4), 11.1 MBq (n = 4), 14.8 MBq (n = 4), 18.5 MBq (n = 4), 22.2 MBq (n = 4), or 25.9 MBq (n = 4) of 131I-labeled B-B4 mAb. This assay was repeated under the same experimental conditions with 25.9 (n = 3) and 37 MBq (n = 3). The maximum tolerated dose (MTD) was determined using the data obtained in the two assays as the dose just below the one at which at least one mouse died or lost more than 10% of its weight before treatment. The mice were weighed weekly for 96 days, and blood samples were taken from the inner border of the eye at 0, 14, 28, 40, 55, and 90 days after 131I-labeled B-B4 mAb injection. Leukocyte and platelet numbers were determined using a cell counter (Melet-Schloesing Laboratories, Cergy-Pontoise France).
An additional RIT experiment was performed under the same conditions as those described for the dose escalation at the MTD (22.2 MBq) (n = 4) and at a lower dose of 14.8 MBq (n = 4) compared to the control group (n = 5). Tumor volumes were measured with a sliding caliper twice a week for 96 days measuring tumor length (L), width (w) and thickness (t). Tumor volume (V) was calculated according to the formula: V = π/6 × L × w × t. In order to increase statistical power, the results of tumor growth assessed by this assay were pooled with those of the corresponding mice groups receiving the same doses in the dose escalation assay. The effect of unlabeled B-B4 mAb (120 μg) and the 131I-labeled isotype-matched mAb control was tested in comparison with a PBS control group in an independent assay.
The parameters used to evaluate the efficacy of each type of treatment were the minimal relative volume (the ratio of the smallest measured tumor volume to the initial tumor volume before treatment) and the event defined as the growth delay (the time required for the tumor to double in size after measurement on the day of treatment). The mean tumor volume was calculated for each group on each day of measurement. Tumor responses were categorized as follows: cure (tumor disappeared with no recurrence at the end of the study 96 days later), complete response (CR) (tumor disappeared for at least 7 days but later re-grew), partial response (PR) (tumor volume decreased by 50% or more for at least 7 days but then re-grew).
Correlations between dose and degree of toxicity (body weight loss, platelets, leukocytes) or efficacy (tumor growth) were made using the nonparametric Spearman's test. Groups of interest (radioimmunotherapy doses) were also compared using the nonparametric ANOVA with Bonferroni correction. Curves for event-free survival (the time required for tumors to reach at least twice the initial volume) were calculated according to the Kaplan-Meier method and compared using the Log-rank test. All analyses were two-sided. P values < 0.05 were considered significant. Analyses were performed using SAS 9.1 (SAS Institute, Cary, NC, USA) and Stata 10.0 SE (StataCorp, College Station, TX, USA). The comparison of the mean tumor volume curves was performed using a nonparametric test with an on-line software from UCL Institut de Statistique (Louvain, Belgium) http://www.stat.ucl.ac.be/ISpersonnel/lecoutre/Tgca/french/help/help.htm.
Immunoreactivity and affinity of radiolabeled B-B4 mAb
Biodistribution of 125I-labeled B-B4 mAb
We further investigated the specificity of B-B4 mAb tumor uptake by comparing it with the biodistribution of an isotype-matched control antibody. To this end, we used the 7D4 IgG1 antibody developed in our laboratory, which does not bind to MDA-MB-468 cells. Tumor uptake measured with the nonspecific 7D4 mAb was subtracted from that detected with the B-B4 mAb in the same assay. The results presented in Figure 3B clearly show that all organs except the tumor displayed an identical B-B4 and 7D4 mAb uptake, with differences that did not exceed 1% ID per gram. Conversely, a clear and specific binding of 125I-labeled B-B4 mAb was observed in the tumor. This specific 125I-labeled B-B4 mAb uptake increased rapidly on the first day post injection and at a lower rate up to 72 h thereafter (Figure 3D). The tumor uptake was long lasting since 7 days after injection, it reached at least 80% of the maximum measured at 72 h (data not shown). Nevertheless, B-B4 tumor uptake was relatively low as compared to other tumor-specific antibodies. Consequently, in this MDA-MB-468 tumor model, the tumor/blood ratio is almost 1:1, as compared to 2:1 in other models. These observations can be explained by the low CD138 expression by this breast cancer cell line, together with the central necrosis in the tumors at the time of the biodistribution study.
RIT toxicity and MTD
The monitoring of animal survival and weight confirmed the mild toxicity of injected activities ranging from 11.1 to 22.2 MBq with no weight loss above 10% and no mortality during the follow-up period. Conversely, higher doses were toxic, with weight loss above 10% and death of all mice within 3 weeks of injection of 37 MBq 131I-labeled B-B4 mAb. In the 25.9-MBq group, one mouse out of seven died during the follow-up and two mice lost more than 10% of their initial weight. Therefore, we defined the 22.2-MBq injected activity of 131I-labeled B-B4 mAb as the MTD.
The MDA-MB-468 cancer cell line is representative of triple-negative breast cancer that has a poor prognosis. As such, it is often used as xenografts in nude mice to test new drugs and therapeutic strategies against breast cancer. Recent studies with a variety of drugs and combination therapies, including antimitotic agents and small molecules inhibiting several signaling pathways resulted in significant tumor growth control but in no real breakthrough. The same model was previously used for RIT studies of the RS7 antibody or its humanized equivalent hRS7 [25, 26], with reported remission rates varying between 9% and 70%. The latter antibody recognizes a pancarcinoma antigen also known as EGP-1 or Trop2. In this paper, we show that when radiolabeled with appropriate iodine isotopes, the anti-CD138 (syndecan-1) antibody B-B4 shows favorable biodistribution, imaging capability, and antitumor properties in the same MDA-MB-468 xenograft model, with three PR, five CR, and three cured animals in a group of eight with established tumors, despite a relatively low expression of the target antigen. In fact, the equilibrium binding assay showed that the number of antigenic sites was as low as 1.2 × 104 per cell, which is consistent with previous reports [27, 24]. This low level of CD138 expression explains the relatively low tumor/blood ratio found in the biodistribution analysis of the B-B4 antibody and the relatively high injected activity (22.2 MBq) required to cure mice from their tumor in the RIT assay. The treatment efficiency is probably explained by the long residence time of activity in the tumor. This was illustrated by immuno-PET imaging where the best tumor images were obtained 8 days after 124I-labeled B-B4 injection. No adverse effects were observed at the MTD defined as 22.2 MBq. Other groups targeted breast cancer xenografts using whole antibodies radiolabeled with 131I and have reported MTD ranging from 7.4 MBq for the 131I-labeled anti-Lewis Y hu3S193 antibody  to 44.4 MBq for the 131I-labeled anti-MUC-1 Mc5 antibody . Interestingly, antibodies targeting the same antigen displayed a very different MTD. Behr and colleagues targeted ACE with the mouse IgG1 mAbs MN-14 and F023C5 and observed an equivalent RIT efficacy on GW-39 colon carcinoma, with an MTD of 9.62 and 22.2 MBq, respectively [30–32]. The 22.2 activity that we determined as the MTD for 131I-labeled B-B4 mAb is in the range of these previously described MTDs.
The choice of the radionuclide for imaging and therapy could influence the efficiency of these approaches. 131I presents some advantages, notably the possibility of imaging and dosimetry and a low activity uptake in the liver. 131I-labeled antibodies are successfully used in consolidation treatment of hepatic metastases of colon cancer after surgical removal of macroscopic lesions  or in the treatment of B cell lymphoma [34–36]. However, mAb labeled with iodine isotopes using the conventional chloramine-T method could result in a loss of efficacy due to the rapid escape of iodotyrosine resulting from the catabolism of the radioiodinated antibody within the lysosomal compartment, especially in the case of internalizing mAb. Several groups have reported that CD138 is internalized. However, the internalization mechanism has been described as clathrin-independent. Internalization has been shown to be fast and to involve a multistep process: ligand binding, clustering, energy-independent lateral movement into detergent-insoluble membrane rafts, and recruitment of actin and tyrosine kinases [37, 38]. This mechanism has been studied by several groups using iodine-labeled ligands of CD138 or of a CD138-FcR fusion protein. Fast degradation of the ligands, like that usually observed for proteins endocytosed via clathrin-coated pits, does not seem to occur after CD138 internalization. In addition, our biodistribution data showed little decrease in tumor activity accumulation up to 96 h, while the circulating antibody concentration decreased at least threefold. In the present study of xenograft MDA MB, 468 PET imaging with 124I-labeled B-B4 confirmed the accessibility of the CD138 antigen and showed a good stability of tumor activity up to 8 days post injection. Thus, deiodination of the radiolabeled antibody seemed to be limited and does not preclude the possibility of performing radioimmunotherapy with 131I-B-B4. Although further studies are needed using a residualizing agent such as that described by Goldenberg and co-workers  or of radioactive metals such as lutetium-177 or yttrium-90 to increase the efficiency of RIT, here we show the potential of targeting CD138 for the treatment of breast cancer in the mouse model with a significant response rate despite the low number of antigen copies expressed by the triple-negative MDA-MB-468 cells.
Targeting CD138 for RIT is attractive since this antigen is associated with an aggressive breast cancer phenotype. CD138 is expressed by about 75% of ER-negative forms of breast cancer , and it is associated with a high histological grade, Ki 67 index, tumor size, and lymph node involvement [8, 40]. RIT targeting CD138 could thus be very useful in the treatment of triple-negative breast cancer that is not eligible for hormone therapy or immunotherapy targeting Her2/neu. TNBC accounts for 10% to 17% of all breast carcinomas and among two thirds of TNBC patients express CD138 on their primary tumor. TNBC are chemosensitive, but TNBC patients with residual disease postchemotherapy have a poor outcome with an increased likelihood of distant recurrence . Targeting tumor cells by RIT with 131I-labeled B-B4 mAb could offer the possibility to achieve responses on chemoresistant cancer cells for patients who relapse after intensive chemotherapy because ionizing radiations act differently on cancer cells. When considering breast cancer irrespective of the ER or PgR expression status, CD138 expression is associated with the worst prognostic marker Her2/neu. Barbareschi and colleagues reported on an additive adverse effect when both Her2/neu and CD138 were overexpressed . Patients suffering from this kind of cancer can be treated by immunotherapy with herceptin associated to radioimmunotherapy with 131I-labeled B-B4 mAb in order to obtain a synergy between the two therapeutic approaches when used in association or as an additional line of treatment for patients who relapse.
It is generally accepted that RIT is more adapted to the systemic treatment of small tumors like metastasis. The expression of CD138 on primary breast tumors and in the corresponding invaded lymph node has been evaluated. The level of expression in invaded lymph nodes is at least equal to that of the primary tumor . The shift of CD138 expression from epithelial cancer cells to fibroblasts of the stroma should not preclude RIT efficacy as long as the overall level of CD138 expression in the tumor ensures sufficient uptake. Indeed, the millimeter range of beta particles enables the irradiation of cells surrounding tumor epithelial cells via the cross-fire effect [42, 43].
RIT targeting CD138 is relevant for the treatment of triple-negative breast cancer and could be applied to patients who relapse after a first-line treatment. The possibility of visualizing tumors by immuno-PET and to perform quantitative imaging prior to therapy provides the advantage of being able to assess CD138 expression in order to conclude on the feasibility of RIT  for each patient.
List of abbreviations
fibroblast growth factors
hepatocyte growth factor
triple-negative breast cancer
vascular endothelial growth factor.
This work was supported by the Grant INCa-ACI200.
- Beauvais DM, Burbach BJ, Rapraeger AC: The syndecan-1 ectodomain regulates alphavbeta3 integrin activity in human mammary carcinoma cells. J Cell Biol 2004,167(1):171–181. 10.1083/jcb.200404171PubMed CentralPubMedView ArticleGoogle Scholar
- Bernfield M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, Zako M: Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 1999, 68: 729–777. 10.1146/annurev.biochem.68.1.729PubMedView ArticleGoogle Scholar
- Jakobsson L, Kreuger J, Holmborn K, Lundin L, Eriksson I, Kjellen L, Claesson-Welsh L: Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis. Dev Cell 2006,10(5):625–634. 10.1016/j.devcel.2006.03.009PubMedView ArticleGoogle Scholar
- Solursh M, Reiter RS, Jensen KL, Kato M, Bernfield M: Transient expression of a cell surface heparan sulfate proteoglycan (syndecan) during limb development. Dev Biol 1990,140(1):83–92. 10.1016/0012-1606(90)90055-NPubMedView ArticleGoogle Scholar
- Ilan N, Elkin M, Vlodavsky I: Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int J Biochem Cell Biol 2006,38(12):2018–2039. 10.1016/j.biocel.2006.06.004PubMedView ArticleGoogle Scholar
- Derksen PW, Keehnen RM, Evers LM, van Oers MH, Spaargaren M, Pals ST: Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. Blood 2002,99(4):1405–1410. 10.1182/blood.V99.4.1405PubMedView ArticleGoogle Scholar
- Yip GW, Smollich M, Gotte M: Therapeutic value of glycosaminoglycans in cancer. Mol Cancer Ther 2006,5(9):2139–2148. 10.1158/1535-7163.MCT-06-0082PubMedView ArticleGoogle Scholar
- Baba F, Swartz K, van Buren R, Eickhoff J, Zhang Y, Wolberg W, Friedl A: Syndecan-1 and syndecan-4 are overexpressed in an estrogen receptor-negative, highly proliferative breast carcinoma subtype. Breast Cancer Res Treat 2006,98(1):91–8. 10.1007/s10549-005-9135-2PubMedView ArticleGoogle Scholar
- Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO: Prognostic markers in triple-negative breast cancer. Cancer 2007,109(1):25–32. 10.1002/cncr.22381PubMedView ArticleGoogle Scholar
- Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W, Toppmeyer D: Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 2006,24(36):5652–5657. 10.1200/JCO.2006.06.5664PubMedView ArticleGoogle Scholar
- Oakman C, Viale G, Di Leo A: Management of triple negative breast cancer. Breast 2010,19(5):312–21. 10.1016/j.breast.2010.03.026PubMedView ArticleGoogle Scholar
- Irvin WJ Jr, Carey LA: What is triple-negative breast cancer? Eur J Cancer 2008,44(18):2799–2805. 10.1016/j.ejca.2008.09.034PubMedView ArticleGoogle Scholar
- Wijdenes J, Vooijs WC, Clement C, Post J, Morard F, Vita N, Laurent P, Sun RX, Klein B, Dore JM: A plasmocyte selective monoclonal antibody (B-B4) recognizes syndecan-1. Br J Haematol 1996,94(2):318–323. 10.1046/j.1365-2141.1996.d01-1811.xPubMedView ArticleGoogle Scholar
- Couturier O, Faivre-Chauvet A, Filippovich IV, Thedrez P, Sai-Maurel C, Bardies M, Mishra Ak, Gauvrit M, Blain G, Apostolidis C, Molinet R, Abbe JC, Bataille R, Wijdenes J, Chatal JF, Chérel M: Validation of 213Bi-alpha radioimmunotherapy for multiple myeloma. Clin Cancer Res 1999,5(10 Suppl):3165s-3170s.PubMedGoogle Scholar
- Supiot S, Faivre-Chauvet A, Couturier O, Heymann MF, Robillard N, Kraeber-Bodere F, Morandaeu L, Mahé MA, Chérel M: Comparison of the biologic effects of MA5 and B-B4 monoclonal antibody labeled with iodine-131 and bismuth-213 on multiple myeloma. Cancer 2002,94(4 Suppl):1202–1209.PubMedView ArticleGoogle Scholar
- DeNardo SJ, O'Grady LF, Richman CM, DeNardo GL: Overview of radioimmunotherapy in advanced breast cancer using I-131 chimeric L6. Adv Exp Med Biol 1994, 353: 203–211.PubMedView ArticleGoogle Scholar
- Schrier DM, Stemmer SM, Johnson T, Kasliwal R, Lear J, Matthes S, Taffs S, Dufton C, Glenn SD, Butchko G, Ceriani RL, Rovira D, Bunn P, Shpall EJ, Bearman SI, Purdy M, Cagnoni P, Jones RB: High-dose 90Y Mx-diethylenetriaminepentaacetic acid (DTPA)-BrE-3 and autologous hematopoietic stem cell support (AHSCS) for the treatment of advanced breast cancer: a phase I trial. Cancer Res 1995,55(23 Suppl):5921s-5924s.PubMedGoogle Scholar
- Behr TM, Sharkey RM, Juweid ME, Dunn RM, Vagg RC, Ying Z, Zhang CH, Swayne LC, Vardi Y, Siegel JA, Goldenberg DM: Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG. J Nucl Med 1997,38(6):858–870.PubMedGoogle Scholar
- Mulligan T, Carrasquillo JA, Chung Y, Milenic DE, Schlom J, Feuerstein I, Paik C, Perentesis P, Reynolds J, Curt G, Goeckeler W, Fordyce W, Cheng R, Riseberg D, Cowan K, O'Shauffnessy J: Phase I study of intravenous Lu-labeled CC49 murine monoclonal antibody in patients with advanced adenocarcinoma. Clin Cancer Res 1995,1(12):1447–1454.PubMedGoogle Scholar
- Oliveras-Ferraros C, Vazquez-Martin A, Lopez-Bonet E, Martin-Castillo B, Del Barco S, Brunet J, Menendez JA: Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin in gefitinib-resistant MDA-MB-468 cells: new prospects in the treatment of triple-negative/basal-like breast cancer. Int J Oncol 2008,33(6):1165–1176.PubMedGoogle Scholar
- Bernardeau K, Gouard S, David G, Ruellan AL, Devys A, Barbet J, Bonneville M, Cherel M, Davodeau F: Assessment of CD8 involvement in T cell clone avidity by direct measurement of HLA-A2/Mage3 complex density using a high-affinity TCR like monoclonal antibody. Eur J Immunol 2005,35(10):2864–2875. 10.1002/eji.200526307PubMedView ArticleGoogle Scholar
- Fraker PJ, Speck JC Jr: Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1,3,4,6-tetrachloro-3a,6a-diphrenylglycoluril. Biochem Biophys Res Commun 1978,80(4):849–857. 10.1016/0006-291X(78)91322-0PubMedView ArticleGoogle Scholar
- Lindmo T, Boven E, Cuttitta F, Fedorko J, Bunn PA Jr: Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Methods 1984,72(1):77–89. 10.1016/0022-1759(84)90435-6PubMedView ArticleGoogle Scholar
- Burbach BJ, Friedl A, Mundhenke C, Rapraeger AC: Syndecan-1 accumulates in lysosomes of poorly differentiated breast carcinoma cells. Matrix Biol 2003,22(2):163–77. 10.1016/S0945-053X(03)00009-XPubMedView ArticleGoogle Scholar
- Shih LB, Xuan H, Aninipot R, Stein R, Goldenberg DM: In vitro and in vivo reactivity of an internalizing antibody, RS7, with human breast cancer. Cancer Res 1995,55(23 Suppl):5857s-5863s.PubMedGoogle Scholar
- Govindan SV, Stein R, Qu Z, Chen S, Andrews P, Ma H, Hansen HJ, Griffiths GL, Horak ID, Goldenberg DM: Preclinical therapy of breast cancer with a radioiodinated humanized anti-EGP-1 monoclonal antibody: advantage of a residualizing iodine radiolabel. Breast Cancer Res Treat 2004,84(2):173–182. 10.1023/B:BREA.0000018417.02580.efPubMedView ArticleGoogle Scholar
- Gotte M, Kersting C, Radke I, Kiesel L, Wulfing P: An expression signature of syndecan-1 (CD138), E-cadherin and c-met is associated with factors of angiogenesis and lymphangiogenesis in ductal breast carcinoma in situ. Breast Cancer Res 2007,9(1):R8. 10.1186/bcr1641PubMed CentralPubMedView ArticleGoogle Scholar
- Clarke K, Lee FT, Brechbiel MW, Smyth FE, Old LJ, Scott AM: Therapeutic efficacy of anti-Lewis(y) humanized 3S193 radioimmunotherapy in a breast cancer model: enhanced activity when combined with taxol chemotherapy. Clin Cancer Res 2000,6(9):3621–3628.PubMedGoogle Scholar
- Peterson JA, Blank EW, Ceriani RL: Effect of multiple, repeated doses of radioimmunotherapy on target antigen expression (breast MUC-1 mucin) in breast carcinomas. Cancer Res 1997,57(6):1103–1108.PubMedGoogle Scholar
- Behr TM, Memtsoudis S, Sharkey RM, Blumenthal RD, Dunn RM, Gratz S, Wieland E, Nebendahl K, Schmidberger H, Goldenberg DM, Becker W: Experimental studies on the role of antibody fragments in cancer radio-immunotherapy: influence of radiation dose and dose rate on toxicity and anti-tumor efficacy. Int J Cancer 1998,77(5):787–795. 10.1002/(SICI)1097-0215(19980831)77:5<787::AID-IJC19>3.0.CO;2-ZPubMedView ArticleGoogle Scholar
- Behr TM, Wulst E, Radetzky S, Blumenthal RD, Dunn RM, Gratz S, Rave-Fränk M, Schmidberger H, Raue F, Becker W: Improved treatment of medullary thyroid cancer in a nude mouse model by combined radioimmunochemotherapy: doxorubicin potentiates the therapeutic efficacy of radiolabeled antibodies in a radioresistant tumor type. Cancer Res 1997,57(23):5309–5319.PubMedGoogle Scholar
- Behr TM, Sgouros G, Vougiokas V, Memtsoudis S, Gratz S, Schmidberger H, Blumenthal RD, Goldenberg DM, Becker W: Therapeutic efficacy and dose-limiting toxicity of Auger-electron vs. beta emitters in radioimmunotherapy with internalizing antibodies: evaluation of 125I- vs. 131I-labeled CO17–1A in a human colorectal cancer model. Int J Cancer 1998,76(5):738–48. 10.1002/(SICI)1097-0215(19980529)76:5<738::AID-IJC20>3.0.CO;2-ZPubMedView ArticleGoogle Scholar
- Liersch T, Meller J, Bittrich M, Kulle B, Becker H, Goldenberg DM: Update of carcinoembryonic antigen radioimmunotherapy with (131)I-labetuzumab after salvage resection of colorectal liver metastases: comparison of outcome to a contemporaneous control group. Ann Surg Oncol 2007,14(9):2577–2590. 10.1245/s10434-006-9328-xPubMedView ArticleGoogle Scholar
- Leahy MF, Turner JH: Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients. Blood 2011,117(1):45–52. 10.1182/blood-2010-02-269753PubMedView ArticleGoogle Scholar
- Leahy MF, Seymour JF, Hicks RJ, Turner JH: Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma. J Clin Oncol 2006,24(27):4418–4425. 10.1200/JCO.2005.05.3470PubMedView ArticleGoogle Scholar
- Jacene HA, Filice R, Kasecamp W, Wahl RL: Comparison of 90Y-ibritumomab tiuxetan and 131I-tositumomab in clinical practice. J Nucl Med 2007,48(11):1767–1776. 10.2967/jnumed.107.043489PubMedView ArticleGoogle Scholar
- Wilsie LC, Gonzales AM, Orlando RA: Syndecan-1 mediates internalization of apoE-VLDL through a low density lipoprotein receptor-related protein (LRP)-independent, non-clathrin-mediated pathway. Lipids Health Dis 2006, 5: 23. 10.1186/1476-511X-5-23PubMed CentralPubMedView ArticleGoogle Scholar
- Fuki IV, Meyer ME, Williams KJ: Transmembrane and cytoplasmic domains of syndecan mediate a multi-step endocytic pathway involving detergent-insoluble membrane rafts. Biochem J 2000,351(Pt 3):607–12.PubMed CentralPubMedView ArticleGoogle Scholar
- Leivonen M, Lundin J, Nordling S, von Boguslawski K, Haglund C: Prognostic value of syndecan-1 expression in breast cancer. Oncology 2004,67(1):11–18. 10.1159/000080280PubMedView ArticleGoogle Scholar
- Barbareschi M, Maisonneuve P, Aldovini D, Cangi MG, Pecciarini L, Angelo Mauri F, Veronese S, Caffo O, Lucenti A, Palma PD, Galligioni E, Doglioni C: High syndecan-1 expression in breast carcinoma is related to an aggressive phenotype and to poorer prognosis. Cancer 2003,98(3):474–83. 10.1002/cncr.11515PubMedView ArticleGoogle Scholar
- Gopal AK, Press OW, Wilbur SM, Maloney DG, Pagel JM: Rituximab blocks binding of radiolabeled anti-CD20 antibodies (Ab) but not radiolabeled anti-CD45 Ab. Blood 2008,112(3):830–835. 10.1182/blood-2008-01-132142PubMed CentralPubMedView ArticleGoogle Scholar
- Maeda T, Desouky J, Friedl A: Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis. Oncogene 2006,25(9):1408–1412. 10.1038/sj.onc.1209168PubMedView ArticleGoogle Scholar
- Mennerich D, Vogel A, Klaman I, Dahl E, Lichtner RB, Rosenthal A, Pohlenz HD, Thierauch KH, Sommer A: Shift of syndecan-1 expression from epithelial to stromal cells during progression of solid tumours. Eur J Cancer 2004,40(9):1373–1382. 10.1016/j.ejca.2004.01.038PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.