title: Increased claudin-4 expression is associated with poor prognosis and high tumour grade in breast cancer.
abstract: The role of intercellular tight junctions in breast epithelial cells is traditionally thought to be in maintaining polarity and barrier function. However, claudin-4, a tight junction protein, is overexpressed in breast tumour cells compared to normal epithelial cells, which generally corresponds to a loss in polarity. The aim of this study was to investigate the distribution and potential clinical value of claudin-4 in breast cancer, and to evaluate its usefulness as a prognostic and predictive biomarker. Expression of claudin-4 was initially examined by Western blot analysis in a cohort of 88 breast tumours, and was found to correlate positively with tumour grade and negatively with ER. Claudin-4 expression was then evaluated by immunohistochemistry in a larger cohort of 299 tumours represented on a tissue microarray. Claudin-4 expression correlated positively with tumour grade and Her2, and negatively with ER. High claudin-4 expression was also associated with worse breast cancer-specific survival (p = 0.003), recurrence-free survival (p = 0.025) and overall survival (p = 0.034). Multivariate analysis revealed that claudin-4 independently predicted survival in the entire cohort (HR 1.95; 95%CI 1.01-3.79; p = 0.047) and in the ER positive subgroup treated with adjuvant tamoxifen (HR 4.34; 95%CI 1.14-16.53; p = 0.032). This relationship between increased claudin-4 expression and adverse outcome was validated at the mRNA level in a DNA microarray dataset of 295 breast tumours. We conclude that high levels of claudin-4 protein are associated with adverse outcome in breast cancer patients, including the subgroup of patients treated with adjuvant tamoxifen.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Lanigan
authors.forename: Eadaoin
authors.initials: E
authors.lastname: McKiernan
authors.forename: Donal J
authors.initials: DJ
authors.lastname: Brennan
authors.forename: Shauna
authors.initials: S
authors.lastname: Hegarty
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
authors.forename: Jean
authors.initials: J
authors.lastname: McBryan
authors.forename: Karin
authors.initials: K
authors.lastname: Jirstrom
authors.forename: Goran
authors.initials: G
authors.lastname: Landberg
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duffy
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D062506:Claudin-4; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D062506:Claudin-4; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C568157:CLDN4 protein, human