A strong correlation between expression of Wntless and of human epidermal growth factor receptor 2 in gastric, ovarian, and breast cancers suggests a novel-signalling pathway involving NFκB and STAT3

The involvement of Wnt signalling in cancers including ovarian, gastric, and breast cancer is well characterised. Wntless (Wls) (also known as GPR177, Evi, and Srt) is a key modulator of Wnt protein secretion, and was recently found to be highly overexpressed in malignant astrocytomas, promoting proliferation, survival, and migration of glioma cells. It was hypothesised that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signalling. Using immunohistochemical analysis of ovarian, gastric, and breast cancer tissue microarrays, we found that Wls was overexpressed in a subset of tumours from each cancer subtype. Wls overexpression was associated with poorer clinical outcomes in gastric cancer. Interestingly, a strong correlation was observed between Wls expression and human epidermal growth factor receptor 2 (HER2) expression. Eight of eight (100%) HER2-positive intestinal gastric carcinomas, five of five (100%) HER2-positive serous ovarian carcinomas, and 41 of 64 (64%) HER2-positive breast carcinomas expressed Wls. This finding has clear biological and clinical implications. HER2 is an important predictive biomarker in breast and gastric cancer for selection of patients likely to respond to trastuzimab. However, a substantial proportion of HER2-positive patients do not respond to this therapy. Recent literature suggested a possible pathway in which Wls and HER2 may be involved via the known mediator of trastuzimab and chemotherapy resistance NFkB, which may explain the low response rate of patients with HER2-positive breast, ovarian, and gastric cancers to agents that target HER2. An in-vitro study has been commenced to try to confirm the existence of this pathway. This study should provide significant insights into the mechanistic association between these important signalling molecules. FUNDING: Queens University Belfast.