title: Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression.
abstract: The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signaling such as ovarian, gastric, and breast cancers. Immunohistochemical analysis using a TMA platform revealed WLS overexpression in a subset of ovarian, gastric, and breast tumors; this overexpression was associated with poorer clinical outcomes in gastric cancer (P=0.025). In addition, a strong correlation was observed between WLS expression and human epidermal growth factor receptor 2 (HER2) overexpression. Indeed, 100% of HER2-positive intestinal gastric carcinomas, 100% of HER2-positive serous ovarian carcinomas, and 64% of HER2-positive breast carcinomas coexpressed WLS protein. Although HER2 protein expression or gene amplification is an established predictive biomarker for trastuzumab response in breast and gastric cancers, a significant proportion of HER2-positive tumors display resistance to trastuzumab, which may be in part explainable by a possible mechanistic link between WLS and HER2.
authors.affiliation: 1] Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, UK [2] Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stewart
authors.affiliation: 1] Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, UK [2] Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: James
authors.affiliation: 1] Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, UK [2] Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors.forename: Glenn W
authors.initials: GW
authors.lastname: McCluggage
authors.affiliation: 1] Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, UK [2] Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: McQuaid
authors.affiliation: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, UK.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Arthur
authors.affiliation: 1] Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, UK [2] Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors.forename: David
authors.initials: D
authors.lastname: Boyle
authors.affiliation: Breast & Ovarian Cancer Programmes, Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Mullan
authors.affiliation: Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors.forename: Darragh
authors.initials: D
authors.lastname: McArt
authors.affiliation: Cancer Science Institute of Singapore, National University Health System & Yong Loo Lin School of Medicine, NUS, Singapore, Singapore.
authors.forename: Benedict
authors.initials: B
authors.lastname: Yan
authors.affiliation: Breast & Ovarian Cancer Programmes, Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Irwin
authors.affiliation: Breast & Ovarian Cancer Programmes, Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, Northern Ireland, UK.
authors.forename: D Paul
authors.initials: DP
authors.lastname: Harkin
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore, Singapore.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhengdeng
authors.affiliation: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, UK.
authors.forename: Chee-Wee
authors.initials: CW
authors.lastname: Ong
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore, Singapore.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore, Singapore.
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.affiliation: 1] Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, UK [2] Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK [3] Cancer Science Institute of Singapore, National University Health System & Yong Loo Lin School of Medicine, NUS, Singapore, Singapore.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D053208:Kaplan-Meier Estimate; D008297:Male; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D046888:Tissue Array Analysis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D043562:Receptors, G-Protein-Coupled; C549111:WLS protein, human; C508053:ERBB2 protein, human