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

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

The main objective of this project has been to investigate the role of the so called Hedgehog pathway in mammary gland stem/progenitor cell fate and cancer development. We have used various mouse models to address these questions. In the mouse models, activation of the Hedgehog pathways is regulated by temporal expression of a protein called GLI1, the effector of the Hedgehog pathway. We have shown that expression of GLI1 in the mammary gland results in tumour formation, even different types of mammary gland tumours, indicating that the expression of GLI1 influences the mammary gland stem cells. The GLI1 induced tumours resemble the hormone receptor expression profile of human triple negative breast cancer. We believe that our mouse model is suitable to address cancer formation and maintenance of mammary tumours depending on Hedgehog pathway activation. To reduce the number of animals included in our research we have established a serial transplantable GLI1 dependent tumour mouse line. To our knowledge, this is the first example of a serial transplantable Hedgehog pathway dependent mammary gland tumour. The serial transplantable tumour line makes it easier to address questions regarding the events involved in early tumour development as well as identifying the cancer initiating cells. Our data suggest that the receptor Lgr5 is expressed in a small subset of cells in the basal cell layer of the large mammary gland ducts. The expression of Lgr5 is increased in the GLI1 induced hyperplastic lesions and tumours. These results are in agreement with our previous observations suggesting that GLI1 induced tumours originate from a cell population in the basal cell layer of the mammary duct. We have shown that expression of GLI1 in a chemical inducible mammary gland cancer model results in faster development of tumours compared to non-GLI1 expressing mice. These results suggest that activation of the Hedgehog pathway can influence tumour development in different classes of breast cancers. Cancer development is a result of several genetic events. We have analysed the GLI1 induced tumours for additional genetic changes and identified genetic events that we will investigate further to determine their role in cancer development and their interplay with the Hedgehog pathway. Based on the results concerning the role of Lgr5 in the mammary gland we decided to generate a new transgenic mouse strain, in which temporal regulation of LGR5 expression is possible. Our results show that expression of LGR5 results in phenotypic changes in several organs. We have shown that expression of GLI1 in mammary epithelial cells can result in tumour formation and increased tumour growth rate in various mouse models. The GLI1 dependent tumours induced without additional chemical treatment appear to be triple negative/basal like and represent a relevant model to investigate the role of the Hedgehog pathway in breast cancer. The GLI1 dependent tumour is established as a serial transplantable mouse line. The stem cell marker Lgr5 is widely expressed in GLI1 induced tumours, suggesting that these tumours are less differentiated. We have generated a new conditional transgenic mouse strain expressing LGR5. Overexpression of LGR5 results in phenotypes in different organs. We believe that the newly develop transgenic mouse model will be an important tool in the future work of addressing the specific function(s) of the LGR5 receptor. In a chemically induced mammary gland cancer model, expression of GLI1 accelerates the tumour growth rate. These results suggest that activation of the Hedgehog pathway can contribute to tumour development under various conditions. Based on our results, we believe that the Hedgehog pathway might constitute a suitable drug target in the subclass of breast cancer with an activated Hedgehog pathway. We will continue our research in this field based on the results and tools developed with the support from the Marie Curie action.

Data: CORDIS, © European Union