Figure 2.

RANK/RANKL-mediated mammary stem cell expansion. RANK is constitutively expressed on the surface of basal and luminal mammary epithelial cells. Progesterone, progestins and prolactin (and possibly other yet unknown factors) induce RANKL expression in progesterone receptor-positive basal mammary cells including mammary stem cells. Binding of RANKL to RANK on luminal epithelial cells takes place in an autocrine manner, whereas RANKL binding to RANK on basal mammary epithelial cells depends on a paracrine activation loop. RANK/RANKL interaction on basal mammary epithelial cells induced further upregulation of RANK and the induction of the IKKα–NFκB–Cyclin D1 signalling axis resulting in proliferation and expansion of mammary stem cells.