Objective Breast cancer is the most common malignancy of women in developed nations. Approximately 1 in 9 women will be diagnosed with breast cancer and many will receive chemotherapy and achieve long-term cancer control. However, in approximately one-third of these women, cancer will recur. This is thought to be due to the presence of chemotherapy-resistant ‘breast cancer stem cells’. Two Polycomb-group proteins, Bmi1 and Ezh2, are frequently over-expressed in breast cancer, suggesting that these epigenetic regulators may play a role in breast tumorigenesis. Interestingly, Bmi1 and Ezh2 are also known to be involved in the maintenance of adult stem cells and in normal mammary gland development. Based on these observations, we postulate that Ezh2 and Bmi1 are critical for maintaining mammary stem cell identity and that mutations leading to the continuous expression of these Polycomb-group genes contribute to the generation of breast cancer stem cells. This project will study the parallels between the role of Polycomb genes in normal mammary stem cell maintenance and their role in breast cancer. We will use novel transgenic mice that express doxycycline-regulatable short hairpin (sh)RNAs to Bmi1 and Ezh2 alone, or in combination with established mammary tumor models that closely resemble human disease. Using these mice, we will investigate whether a) knockdown of Bmi1 and Ezh2 causes a regression of the normal and/or cancer stem cell compartment and b) whether this can be exploited to eradicate mammary tumors. Understanding the way in which Ezh2 and Bmi1 exert their effects may lead to novel targeted therapies for breast cancers, which may lead to the eradication of those cells that have the capacity to initiate tumor recurrence. We are confident that the proposed studies, many of which are already well in progress, will provide new insight into the factors that contribute to cancer initiation and maintenance and will have important implications for cancer treatment. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicineoncologybreast cancernatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesgeneticsRNA Keywords Mouse models breast cancer cancer stem cells polycomb group genes tumor therapy Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-IIF-2008 - Marie Curie Action: "International Incoming Fellowships" Call for proposal FP7-PEOPLE-IIF-2008 See other projects for this call Funding Scheme MC-IIF - International Incoming Fellowships (IIF) Coordinator STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS Address Plesmanlaan 121 1066 CX Amsterdam Netherlands See on map Region West-Nederland Noord-Holland Groot-Amsterdam Activity type Research Organisations Administrative Contact Henri Van Luenen (Dr.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution € 167 157,36
