title: Glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) expression correlates with malignant choline phospholipid metabolite profiles in human breast cancer.
abstract: Altered choline phospholipid metabolism is a hallmark of cancer, leading to malignant choline metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines (n = 8 and n = 10) and primary human breast tumor samples (n = 19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline phospholipid metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER(-)) compared with weakly malignant estrogen receptor positive (ER(+)) human breast cancer cells (p = 0.027) and breast tumors from patients (p = 0.015). GDPD5 showed significantly positive correlations with PC (p < 0.001), total choline (tCho) (p = 0.007) and PC/GPC (p < 0.001) levels in human breast tumors. GDPD5 showed a trend towards a negative correlation with GPC levels (p = 0.130). Human breast cancers with malignant choline metabolite profiles consisting of low GPC and high PC levels highly co-expressed GDPD5, choline kinase alpha (CHKA) and phosphatidylcholine-specific phospholipase D1 (PLD1), whereas cancers containing high GPC and relatively low PC levels displayed low co-expression of GDPD5, CHKA and PLD1. GDPD5, CHKA and PLD1 were significantly overexpressed in highly malignant ER(-) tumors in our patient cohort. Our study identified GDPD5 as a GPC-PDE that probably participates in the regulation of choline phospholipid metabolism in breast cancer, which possibly occurs in cooperation with CHKA and PLD1.
authors.affiliation: The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Cao
authors.forename: Mailin
authors.initials: M
authors.lastname: Döpkens
authors.forename: Balaji
authors.initials: B
authors.lastname: Krishnamachary
authors.forename: Farhad
authors.initials: F
authors.lastname: Vesuna
authors.forename: Mayur M
authors.initials: MM
authors.lastname: Gadiya
authors.forename: Per E
authors.initials: PE
authors.lastname: Lønning
authors.forename: Zaver M
authors.initials: ZM
authors.lastname: Bhujwalla
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Gribbestad
authors.forename: Kristine
authors.initials: K
authors.lastname: Glunde
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002457:Cell Extracts; D045744:Cell Line, Tumor; D002794:Choline / Q000378:metabolism*; D002797:Choline Kinase / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055442:Metabolome; D008875:Middle Aged; D019906:Nuclear Magnetic Resonance, Biomolecular; D010739:Phospholipase D / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D010743:Phospholipids; D012333:RNA, Messenger; D002797:Choline Kinase; D010727:Phosphoric Diester Hydrolases; C020677:glycerophosphocholine phosphodiesterase; D010739:Phospholipase D; C106801:phospholipase D1; D002794:Choline