Frizzled receptor 6 and risk of metastatic recurrence in early triple negative breast cancer

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University London.WNT lipoglycoproteins (WNTs) modulate a plethora of cellular functions through the activation of the family of frizzled receptors (FZDs). Deregulation in components of the WNT signalling pathways is often observed in human cancers and associated with uncontrolled proliferation and metastasis. Frizzled receptor 6 (Fzd6), one of the ten human FZDs, is frequently overexpressed in cancer, but its role in tumorigenesis is still unclear. In this study we investigated the role Fzd6 in breast cancer. We found that expression of Fzd6 predicts distant relapse in patients with localised breast cancers, particularly in those bearing the triple negative subtype. Using a loss of function approach, we demonstrated that Fzd6 is important to regulate motility and invasion of breast cancer cells in vitro and in vivo. Indeed, Fzd6 regulates the tropism of breast cancer cells the bone, liver and heart of mice. Mechanistically, we found that Fzd6 signalling activates the small GTPase Rho and is important in the organisation of the fibronectin matrix. Both Rho and fibronectin have been previously implicated in the development of metastasis in different systems. All together, these results demonstrate that Fzd6 is an important driver of metastatic spread and a predictive marker of metastatic relapse in breast cancer patients. Fzd6 could therefore be used as a biomarker and target in metastatic breast cancer