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Immunoglobulin Heavy Chain Locus Events and Expression of Activation-Induced Cytidine Deaminase in Epithelial Breast Cancer Cell Lines

¹ Genetic Vaccine Group and ² Cancer Sciences Division, School of Medicine, University of Southampton, Southampton, United Kingdom

Requests for reprints: Surinder S. Sahota, Molecular Immunology Group, Tenovus Laboratory, Cancer Sciences Division, School of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, United Kingdom. Phone: 44-2380-798768; Fax: 44-2380-701385; E-mail: s.s.sahota{at}soton.ac.uk.

When cells transform, phenotypic and genetic profiles can be dramatically altered. Nevertheless, a recent report identifying IgG in breast cancer cells was unexpected, revealing differentiation features normally associated with B lymphocytes. To extend these findings, we focused on immunoglobulin variable (V) region gene analysis using well-defined breast cancer cell lines expressing the epithelial marker, epithelial cell adhesion molecule (EpCAM). V_H gene transcripts were identifiable by nested reverse transcription-PCR either as single or dual V, diversity (D), and joining (J) rearrangements in four of six lines, most being potentially functional. V(D)J transcripts were observed in sequential cultures, indicating stable expression. To exclude coexisting lymphocytes, each cell line was shown to be EBV negative, with CD19/CD20 and cytoplasmic/surface immunoglobulin also absent by flow cytometry. Identified V_H transcripts were then sought in individual tumor cells, isolated as EpCAM⁺ single cells by flow cytometry. Importantly, in three of three selected cell lines, V_H genes were identifiable in a significant fraction (32%) of single cells. In five of six identified V_H genes, somatic mutations were apparent with no intraclonal variation, indicating cessation of mutational activity. V_H transcripts were pre- and post-isotype switch, with activation of switch events evident from expressed germ-line switch transcripts in two of six lines. Strikingly, six of six cell lines expressed activation-induced cytidine deaminase (AID) essential for mutational and switch activity. These data suggest either a de novo rearrangement and modification of V_H genes in epithelial tumor cells or assimilation of lymphocyte-derived chromatin. Constitutive AID activation in malignant epithelial cells further raises a potential for inducing aberrant mutational activity. (Cancer Res 2006; 66(8): 3996-4000)

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