A Novel Gene (PLU-1) Containing Highly Conserved Putative DNA/Chromatin Binding Motifs Is Specifically Up-regulated in Breast Cancer

Abstract

The genetic changes that occur in cancer, whether these be mutations or alterations in levels of gene expression, become evident as changes in the phenotype of a specific cell type. In characterizing these phenotypic changes in malignancy, it is therefore important to work with the appropriate cells or cell lines. Breast cancers show the phenotype of the luminal epithelial cell (1), which can be cultured from milk, and cell lines have been developed from these milk cells which retain the luminal phenotype (2). One of these cell lines (MTSV1-7) has been used to look at the effect of overexpression of various oncogenes and proto-oncogenes on the behavioral properties of this cell type (3, 4).Overexpression of the c-ErbB2 receptor has been observed in a proportion of breast cancers and found to correlate with a poor prognosis (5), making signaling from this receptor an important parameter for investigation. To study the function of c-ErbB2 in human mammary epithelial cells, the receptor was overexpressed in MTSV1-7 cells to produce the ce-1 cell line (3). Unlike other receptors in the ErbB family, the c-ErbB2 homodimer has no known ligand, although c-ErbB2 can function as a heterodimeric receptor for the heregulin family of ligands with c-ErbB3 or c-ErbB4 or for EGF with c-ErbB1 (6 -9). Signaling from c-ErbB2 in overexpressing cells is, however, thought to be constitutive, operating through autophosphorylation of the homodimer, which forms because of overexpression (10).To look for genes whose expression is reversibly regulated by c-ErbB2 signaling as a homodimer, we have down-regulated c-ErbB2 phosphorylation using an antibody that has been shown to inhibit signaling from the receptor in breast cancer cell lines (11). In the humanized form (12), the antibody is under investigation in the clinic for the treatment of breast cancer (13). cDNAs prepared from ce-1 cells, treated or untreated with the antibody 4D5, were used to differentially screen filters from a fetal brain library using a computerized analysis (14), and a partial clone was isolated representing a novel sequence. Clones covering the full-length sequence (6.4 kb) 1 of the novel PLU-1 gene 2 were subsequently isolated by screening a breast cancer cDNA library.

Retinoblastoma-binding protein 2-homolog 1: a retinoblastoma-binding protein downregulated in malignant melanomas

“…7,8 More detailed data on the expression of most RBPs in normal and neoplastic tissues are still lacking. While some RBPs, that is, PLU-1 and RBP-1, seem to play a role in breast cancer, 9,10 a possible impact of many other RBPs including RBP2-H1 on human cancer progression has not been investigated, yet.…”

T cells reactive with HLA‐A*0201 peptides from the histone demethylase JARID1B are found in the circulation of breast cancer patients

“…However, only JARID1B has been reported to be expressed in cancer. 7,9,11,14 JARID1A shows a wider range of expression, and JARID1C is associated with neural development and X-linked mental retardation. 37 The JARID1B HLA-A*0201 epitopes analyzed here were selected for showing the least conservation between the other JARID1 proteins, and any T cells generated should not react with the other members of the JARID1 family.…”

“…[7][8][9][10][11] More recently, expression of this gene in other cancers (bladder, lung, AML) has been reported and the restricted expression in normal tissues confirmed 12 suggesting a specific involvement of PLU-1/JAR-ID1B in malignancy. Moreover, the restricted expression in adult tissues makes the protein a potential therapeutic target, particularly in women.…”

“…9 In multiple experiments from different donors, none of the peptide-specific T cell cultures demonstrated reactivity against the unpulsed MCF-7 in spite of the fact that MCF-7 cells express JARID1B (see Fig. 2a for an example).…”

“…[7][8][9][10] The expression of JARID1B RNA is highest in ER þ ductal carcinomas (www.oncomine.org/), being less well expressed in lobular carcinomas 8 (see Fig. 1).…”