Dysregulation of Hedgehog, Wnt and Notch signalling pathways in breast cancer

Abstract

There has been a significant decrease in mortality from breast cancer in the last two decades. This has been attributed to the introduction of mammographic screening and to the development of specialised therapies, notably anti-estrogens such as tamoxifen in estrogen receptor (ER) positive tumours, and adjuvant chemotherapy. More recently monoclonal antibodies such as trastuzumab directed against Her2- overexpressing tumours show significant promise in improving outcome from this aggressive subtype. While there have been significant advances, a number of clinical challenges still remain, particularly development of targeted therapies for other forms of breast cancer lacking ER or Her2, such as the aggressive basal-like carcinomas. Identification of new therapeutic targets in poor prognosis groups will be critical to further improvements in breast cancer treatment. Proper functioning of the Hedgehog, Notch and Wnt signalling pathways is required for normal development during early life and these pathways also play a key role in regulation and maintenance of stem cells. Increasing evidence implicates dysregulation of these pathways in the development and progression of a number of malignancies, including breast cancer. This review presents the current evidence for aberrations in these pathways in breast cancer and proposes that the Hedgehog, Notch and Wnt signalling pathways may represent novel therapeutic targets.