Wnt-5a Signalling in Human Mammary Cells: Implications for the Development of Breast Cancer

Abstract: The Wnt-5a gene encodes a secreted protein that regulates several normal processes in embryonic and adult tissues by as yet unknown mechanisms. Expression of Wnt-5a protein does not cause cell transformation, but it instead counteracts the effects induced by transforming Wnts. Inasmuch as Wnt-5a can activate the Wnt/beta-catenin signalling pathway, we performed experiments to determine whether molecules participating in this pathway were modified in breast tumours. Thirteen percent of the tumours we studied showed accumulation of beta-catenin protein but no mutations in the beta-catenin gene or defects in APC protein. Moreover, the human dishevelled gene (DVL-3) was rarely activated in the examined tumours. To elucidate the mechanisms of action of Wnt-5a, we studied the response of breast epithelial cells to overexpression or inhibition of this protein. Our results demonstrate that Wnt-5a is a co-factor that is needed to activate the collagen-binding discoidin domain receptor 1. In addition, the Wnt-5a protein exhibited activities involved in positive regulation of cell adhesion and negative regulation of cell migration. To determine whether the biological activities of Wnt-5a are linked to the development of breast cancer, we evaluated levels of this protein in invasive breast tumours. We found that expression of Wnt-5a had been lost in 44% of the studied carcinomas. This loss was significantly associated with higher histological grade and absence of estrogen and progesterone receptors, and proved to be an independent and powerful predictor of early relapse. Thus our data support the notion that Wnt-5a is a tumour suppressor, and that lack of this protein increases the risk of recurrent breast disease.