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[Google Scholar] [32] Stott DI, McIntyre D. unaffected by therapeutic vaccination. The antibody response exhibited restricted expansion of the Immunoglobulin (Ig) variable (V)-gene repertoire by ErbB-2 specific B cells compared with the non-antigen specific B cell pool and control mice. The serum antibody profile was comparable in therapeutically injected mice without any effect on tumour burden. Keywords: Breast malignancy, ErbB-2, Tolerance, Mouse model, Antibody, V-genes, Repertoire Introduction Breast cancer is the commonest cancer in women worldwide and also affects men, albeit with c.100-fold lower incidence. ErbB-2 (Neu/HER2) is usually overexpressed at high transcript and protein levels in 20-30% of primary human breast cancers and is associated with tumour progression, invasion, metastases and poor prognosis [1]. The 185 kD transmembrane ErbB2 protein, is usually also associated JTE-952 with other human malignancies, including ovarian cancer, and often results in significantly poor prognosis compared to their non-ErbB-2 expressing counterparts [2]. It is one of the four members of the Epidermal growth Factor Receptor (EGFR) tyrosine kinase family [3] and is expressed in moderate to low concentration in healthy adult tissue [4]. Ligand mediated heterodimerisation with other members of the family triggers intrinsic tyrosine phosphorylation of ErbB-2 leading to activation and downstream effects of cell proliferation, survival and transformation [5] although no natural ligand of ErbB-2 has been identified so far. Overexpression in malignancies promotes spontaneous dimerisation even in the absence of ligands and leads to constitutive activation of the signalling pathways [6]. Apparently, the partner of dimerisation directs differential downstream effects on tumour cells. Heregulin ligand-mediated complex of ErbB-2 with ErbB3 or ErbB4 inhibits tumour proliferation but increases invasiveness [7]. ErbB-2 ectodomain is usually cleaved by metalloproteases leaving the constitutively active, truncated, intracellular tyrosine kinase receptor in the tumour tissue [8]. This circulating serum ErbB-2, a 97 to 115 kD oncoprotein, is usually detectable in patients as a prognostic disease marker [9]. In ErbB-2 associated breast cancer patients, a spontaneous anti-ErbB-2 immune response against this autologous, native JTE-952 ErbB-2 ectodomain has been documented in both early and late stage metastatic diseases [10-12]. Though there is coexistence of ErbB-2 antigen and antibody in patients, monoclonal antibody therapy has proven to be effective against disease progression in ErbB-2-expressing human breast malignancy and transplantable animal JTE-952 models. The humanised anti-ErbB-2 recombinant monoclonal antibody trastuzumab (Herceptin?) is already in clinical practice. Moreover, in transgenic mice, ErbB-2 vaccination induced anti-tumour immunity mediated by both humoral and cellular arms [13] along with a modulating effect on oncogenic activity of tumour associated ErbB-2 [4]. The down modulating effect on ErbB-2 expression by anti-ErbB-2 monoclonal antibody is also evident in transformed cell lines[14]. Whereas most previous studies have relied on ectopic transplanted tumour models, to JTE-952 reproduce the human breast cancer scenario it is important to study the effects of the anti-ErbB-2 immune response on spontaneous development of eutopic mammary carcinoma. Several JTE-952 genetic and non-genetic vaccination strategies targeted against ErbB-2 exhibited various degrees of success in animal models. Peptide vaccines like E75, GP2, AE37, and Ii-Key [15] and peptide-pulsed autologous dendritic cell vaccine (NCT00923143) are in Cish3 clinical trials (www.clinicaltrials.gov). These peptides evoke cytotoxic T cell mediated immunity and are restricted by the requirement for HLA matching. Naked DNA (NCT00393783) and vaccine formulations (NCT00197522, NCT00485277) made up of autologous dendritic cells transfected with ErbB-2 DNA are under clinical investigation in the hope of circumventing HLA restriction, with limited success to date. In a transplanted tumour animal model, vaccination with the ErbB-2 protein ectodomain fused with a T helper cell epitope was successful in overcoming tolerance and retarding progression of transplantable tumours [16]. However, the immune response to tumours transplanted at ectopic sites differs qualitatively from the response to.