title: hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan.
abstract: hAG-2 and hAG-3 are recently discovered human homologues of the secreted Xenopus laevis proteins XAG-1/2 (AGR-1/2) that are expressed in the cement gland, an ectodermal organ in the head associated with anteroposterior fate determination during early development. Although the roles of hAG-2 and hAG-3 in mammalian cells are unknown, both proteins share a high degree of protein sequence homology and lie adjacent to one another on chromosome 7p21. hAG-2 mRNA expression has previously been demonstrated in oestrogen receptor (ER)-positive cell lines. In this study, we have used real-time quantitative RT - PCR analysis and immunohistochemistry on tissue microarrays to demonstrate concordant expression of hAG-2 and hAG-3 mRNA and protein in breast tumour tissues. Tumour expression of both genes correlated with OR (hAG2, P=0.0002; hAG-3, P=0.0012), and inversely correlated with epidermal growth factor receptor (EGFR) (P=0.003). Yeast two-hybrid cloning identified metastasis-associated GPI-anchored C4.4a protein and extracellular alpha-dystroglycan (DAG-1) as binding partners for both hAG-2 and hAG-3, which if replicated in clinical oncology would demonstrate a potential role in tumour metastasis through the regulation of receptor adhesion and functioning. hAG-2 and hAG-3 may therefore serve as useful molecular markers and/or potential therapeutic targets for hormone-responsive breast tumours.
authors.affiliation: Oxford Glycosciences, Abingdon, Oxon, UK.
authors.forename: G C
authors.initials: GC
authors.lastname: Fletcher
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: K
authors.initials: K
authors.lastname: Tyson
authors.forename: P J
authors.initials: PJ
authors.lastname: Adam
authors.forename: M
authors.initials: M
authors.lastname: Schenker
authors.forename: J A
authors.initials: JA
authors.lastname: Loader
authors.forename: L
authors.initials: L
authors.lastname: Daviet
authors.forename: P
authors.initials: P
authors.lastname: Legrain
authors.forename: R
authors.initials: R
authors.lastname: Parekh
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: J A
authors.initials: JA
authors.lastname: Terrett
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D049030:Dystroglycans; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D054806:Magainins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020161:Physical Chromosome Mapping; D010940:Plant Proteins; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020798:Two-Hybrid System Techniques; D029867:Xenopus Proteins
chemical_list: C472588:AGR3 protein, human; D023181:Antimicrobial Cationic Peptides; C401412:C40.4 protein, Solanum demissum; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D058851:GPI-Linked Proteins; C472589:LYPD3 protein, human; D054806:Magainins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D010940:Plant Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D029867:Xenopus Proteins; C053301:magainin 2 peptide, Xenopus; D049030:Dystroglycans