title: High level PHGDH expression in breast is predominantly associated with keratin 5-positive cell lineage independently of malignancy.
abstract: We have previously reported the 2D PAGE-based proteomic profiling of a prospective cohort of 78 triple negative breast cancer (TNBC) patients, and the establishment of a cumulative TNBC protein database. Analysis of this database identified a number of proteins as being specifically overexpressed in TNBC samples. One such protein was D-3-phosphoglycerate dehydrogenase (Phgdh), a candidate oncogene. We analysed expression of Phgdh in normal and TNBC mammary tissue samples by 2D gel-based proteomics and immunohistochemistry (IHC), and show here that high-level expression of Phgdh in mammary epithelial cells is primarily associated with cell lineage, as we found that Phgdh expression was predominant in CK5-positive cells, normal as well as malignant, thus identifying an association of this protein with the basal phenotype. Quantitative IHC analysis of Phgdh expression in normal breast tissue showed high-level expression of Phgdh in normal CK5-positive mammary epithelial cells, indicating that expression of this protein was not associated with malignancy, but rather with cell lineage. However, proteomic profiling of Phgdh showed it to be expressed in two major protein forms, and that the ratio of expression between these variants was associated with malignancy. Overexpression of Phgdh in CK5-positive cell lineages, and differential protein isoform expression, was additionally found in other tissues and cancer types, suggesting that overexpression of Phgdh is generally associated with CK5 cells, and that oncogenic function may be determined by isoform expression.
authors.affiliation: Cancer Proteomics, Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark; Danish Centre for Translational Breast Cancer Research (DCTB), Copenhagen, Denmark.
authors.forename: Irina
authors.initials: I
authors.lastname: Gromova
authors.affiliation: Cancer Proteomics, Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark; Danish Centre for Translational Breast Cancer Research (DCTB), Copenhagen, Denmark.
authors.forename: Pavel
authors.initials: P
authors.lastname: Gromov
authors.affiliation: Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Honma
authors.affiliation: Department of Pathology, Yale University Medical School, New Haven, USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Pathology, Yale University Medical School, New Haven, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rimm
authors.affiliation: Department of Pathology, The Centre of Diagnostic Investigations, Copenhagen University Hospital, Denmark.
authors.forename: Maj-Lis Møller
authors.initials: ML
authors.lastname: Talman
authors.affiliation: Department of Pathology, The Centre of Diagnostic Investigations, Copenhagen University Hospital, Denmark.
authors.forename: Vera Timmermans
authors.initials: VT
authors.lastname: Wielenga
authors.affiliation: Danish Centre for Translational Breast Cancer Research (DCTB), Copenhagen, Denmark; Section for Molecular Disease Biology and Sino-Danish Breast Cancer Research Centre, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: jomo@sund.ku.dk.
authors.forename: José M A
authors.initials: JM
authors.lastname: Moreira
mesh_terms: D001940:Breast / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D053555:Keratin-5 / Q000378:metabolism*; D061986:MCF-7 Cells; D008875:Middle Aged; D050543:Phosphoglycerate Dehydrogenase / Q000378:metabolism*; D020543:Proteome / Q000032:analysis / Q000378:metabolism; D046888:Tissue Array Analysis; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D007527:Isoenzymes; D053555:Keratin-5; D020543:Proteome; D050543:Phosphoglycerate Dehydrogenase
keywords: Breast cancer; Phgdh; Proteomics; Serine biosynthesis; “Basal-type” breast cancer