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IS-TOPP-Toppfinans. av M.Curie-stipend

Understanding Hedgehog signalling in breast cancer and mammary gland stem cells using tissue specific expression of Gli1

Tildelt: kr 0,20 mill.

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 int o 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 t he 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 t he 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 r elevant 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 change s 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 tumorig enecity 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.

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IS-TOPP-Toppfinans. av M.Curie-stipend

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