Cytoplasmic localization of B-catenin is a marker of a poor outcome in breast cancer patients
� catenin is involved in cell adhesion via 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 have been undertaken in breast cancer with contradictory associations reported between � catenin expression, clinicopathological parameters and disease outcome. We undertook an immunohistochemical study measuring the levels and subcellular localization of � catenin in 292 invasive ductal breast cancers with known treatment and outcome. No association with outcome was observed for cytoplasmic or membrane expression alone, however a shift from membrane to cytoplasm expression (?MTC? score), a continuous variable measuring the relative ratio of cytoplasmic and membranous staining, was associated with worse outcome in univariate analysis (p=0.004), and approached significance in a multivariate analysis model that included lymph node, PR and HER2 status (p=0.054). Therefore MTC score was used for further statistical analyses due to the importance of both subcellular location and levels of expression of � catenin. An association was identified between a shift to high cytoplasmic expression i.e. low ?MTC score? and high tumour grade (p=0.004), high proliferation rate i.e. Ki67 positive (p=0.0001), negative ER (p=0.005), positive HER2 (p=0.01) status and an active PI3K pathway (p=0.005), measured as PIK3CA mutations (p=0.05) or PTEN loss (p=0.05). A shift to low cytoplasmic expression (high MTC score) was associated with the Luminal A subtype (p=0.004). In conclusion, a shift in � catenin from a predominantly membrane to cytoplasmic localisation is associated with an adverse outcome in breast cancer, which may be of mechanistic significance in the disease process.
|Authors||Lopez-Knowles, E., Zardawi, S.J., McNeil, C.M., Millar, E.K.A., Crea, P., Musgrove, E.A., Sutherland, R.L.; O'Toole, S.A.|
|Responsible Garvan Author|
|Publisher Name||CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION|
|URL link to publisher's version||http://cebp.aacrjournals.org/content/19/1/301|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10502|