title: Cytoplasmic localization of beta-catenin is a marker of poor outcome in breast cancer patients.
abstract: Beta-catenin is involved in cell adhesion through catenin-cadherin complexes and as a transcriptional regulator in the Wnt signaling pathway. Its deregulation is important in the genesis of a number of human malignancies, particularly colorectal cancer. A range of studies has been undertaken in breast cancer, with contradictory associations reported among beta-catenin expression, clinicopathologic variables, and disease outcome. We undertook an immunohistochemical study measuring the levels and subcellular localization of beta-catenin in 292 invasive ductal breast cancers with known treatment and outcome. No association with breast cancer-specific death was observed for cytoplasmic or membrane expression alone; however, a continuous score representing both locations (membrane minus cytoplasmic expression: MTC score) was associated with a worse outcome in univariate analysis (P = 0.004), and approached significance in a multivariate analysis model that included lymph node, progesterone receptor (PR), and HER2 status (P = 0.054). Therefore, the MTC score was used for further statistical analyses due to the importance of both the subcellular location and the levels of expression of beta-catenin. An association was identified between high cytoplasmic expression (low MTC score), and high tumor grade (P = 0.004), positive Ki67 (P = 0.005), negative estrogen receptor (ER) (P = 0.005), positive HER2 (P = 0.04) status, and an active phosphoinositide 3-kinase pathway (P = 0.005), measured as PIK3CA mutations (P = 0.05) or PTEN loss (P = 0.05). Low cytoplasmic expression (high MTC score) was associated with the luminal A subtype (P = 0.004). In conclusion, a low beta-catenin MTC score is associated with an adverse outcome in breast cancer, which may be of mechanistic significance in the disease process.
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Elena
authors.initials: E
authors.lastname: López-Knowles
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Zardawi
authors.forename: Catriona M
authors.initials: CM
authors.lastname: McNeil
authors.forename: Ewan K A
authors.initials: EK
authors.lastname: Millar
authors.forename: Paul
authors.initials: P
authors.lastname: Crea
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Musgrove
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Sandra A
authors.initials: SA
authors.lastname: O'Toole
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000401:mortality; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human