The epithelial compartments of the mammary gland are thought to be derived from a tissue stem cell capable of self-renewal and differentiating into all cellular lineages of the mammary gland. Detailed studies of normal and tumorigenic breast stem cells have proven rather cumbersome since these cells are rare and a high degree of purification is needed. Several approaches to isolate mammary stem cells are based on the use of relatively unspecific surface markers, which are also expressed on differentiated cells.Lgr5 is a marker of stem cells in several different organs, such as the intestine, the stomach and the skin. Recently, another Lgr family member, Lgr6, could be identified as a marker of a second epidermal stem cell population in the skin than can regenerate all cellular lineages of the skin.The high homology between Lgr5 and Lgr6 and the fact that both receptors represent stem cell markers in the skin, suggest that Lgr6 could also specifically mark certain stem cell populations in other tissues. Indeed, the host laboratory has found prominent expression of Lgr6 cells in brain, mammary gland and lung. Noteworthy, the hair follicle and the mammary gland are both ectodermal-derived appendages that show strong similarities as regards the molecular mechanisms controlling their formation, maintenance and cellular turn-over.Lgr6 shows a conserved upregulation between human and mouse mammary stem cell fractions. In line with the notion that normal stem cells can be a source of cancer stem cells, breast cancer tissues shows an overexpression of Lgr6, similar to skin cancer cells.The first aim of the proposed project is to clarify the nature and identity of mammary gland cells that express the putative stem cell marker Lgr6.Secondly, this project will determine the functional role of Lgr6 in regard to breast stem cell maintenance, progenitor cell commitment and cancer development.