MAMMAHOGLGR · Understanding Hedgehog signalling in breast cancer and mammary gland stem cells using tissue specific expression of Gli1 the main effector of the Hedgehog pathway

Only a subset of tumour cells is capable of giving rise to new tumours. These so called “tumour stem-cells” are functionally similar to adult stem cells and have been identified in tumours of several tissues. Whether transformation of adult stem cells into tumour stem cells is the event leading to the disease is not clear. Alternatively, tumours could arise from the population of committed progenitors, which have de novo acquired self-renewal properties. The aim of the proposed project is to investigate the role of Hedgehog (Hh) signalling in mammary gland stem/progenitor cell fate and cancer development. The following questions will be addressed: 1. Does induction of Gli1 expression expand the stem/progenitor cell population in the mammary gland and are the functional properties of these cells changed? 2. Does induction of Gli1 expression expand the population of Lgr5+ cells in Gli expressing mammary glands and Gli1 induced tumours? 3. Does induction of Gli1 expression result in additional genetic changes relevant for tumour formation? 4. Does induction of Hh-signalling in Lgr5+ mammary cells cause tumour formation? 5. Would prevention of Gli activation with small molecule inhibitors like GANT61 prevent mammary cancer formation? The activity of the Hh pathway is required for growth of a variety of tumours, including breast cancer. We propose to use tetracycline-controlled conditional expression of Gli1, the main effector of the Hh-signalling pathway, in mouse mammary gland as a model system. The dynamic changes in the stem/progenitor cell population will be monitored after induction of Gli1 expression. Stem cells will be sorted based on known markers, including the orphan G protein coupled receptor Lgr5. The role of Hh signalling in Lgr5+ cells and the tumorigenecity of Lgr5+ cells will be addressed. This project will contribute to our understanding of breast cancer development and have implications on future therapeutic strategies of mammary cancer.