Role of Wnt-5a in breast cancer

Sammanfattning: Breast cancer is one of the most common cancer forms in the industrialized world. Only in Sweden, nearly 6000 women are diagnosed with breast cancer each year and 1/3 of them eventually succumb to the disease. Wnts are a family of genes that have been implicated in many human tumours, so far mainly studied in colorectal cancer where activated Wnt signalling occurs in a vast majority of tumours. Whereas the oncogenic Wnt-1 is the main Wnt protein investigated in breast cancer, very little work has been focused on Wnt-5a, a protein supposedly antagonizing the oncogenic effects of Wnt-1. We found that Wnt-5a protein expression is reduced in many invasive breast carcinomas and that reduced Wnt-5a expression in the primary tumour strongly correlates with an increased risk of metastatic disease and shorter survival. The expression of Wnt-5a protein co-varies with that of Syk, a tyrosine kinase that is lost in up to 30% of invasive breast carcinomas and associated with poor prognosis. Furthermore, patients with tumours expressing both Wnt-5a and Syk had a significantly better prognosis as compared with those displaying loss of either of or both proteins. Despite the co-expression, loss of Wnt-5a and Syk protein appear to be regulated at the translational and transcriptional levels, respectively. In normal breast epithelium, Wnt-5a is important for cell-ECM adhesion and activation of the collagen receptor DDR1. Restitution of Wnt-5a signalling in breast tumour cells confer better adhesion and ability to activate DDR1 as well as a less malignant-looking phenotype. In human breast epithelial cells Wnt-5a activates the canonical b-catenin pathway as well as the non-canonical Ca2+/calmodulin and planar cell polarity (PCP) pathways. The latter involves Src, the RhoGTPase Cdc42 and JNK and was shown to counteract the NFAT activation induced by the Ca2+/calmodulin pathway. The collagen-induced activation of DDR1, which also is Src-dependent, appears to be mediated by the PCP pathway. Wnt-5a signalling is thus involved in the activation of DDR1 as well as in hampering NFAT activity, both of which affect the migratory capacity of tumour cells. Consequently, the increased metastatic potential of breast tumours with low Wnt-5a expression could be due to inactivation of DDR1 or enhanced NFAT activation. The results presented in this thesis thus imply that Wnt-5a contains metastasis-suppressing activity in breast cancer. Depending on the cellular effects through which Wnt-5a mediates its function, reconstitution of Wnt-5a signalling might have future therapeutical implications.