How the mammary gland develops from buds in the ventral embryonic epidermis and how subsequent ducts develop are poorly understood. Now Hens et al.() report on the role that parathyroid hormone-related protein (PTHrP) and its cooperation with BMP signalling plays in some of these events. By studying various individual and combined mutant and reporter mice, the authors discovered that PTHrP secreted by mammary epithelial cells present in mammary buds leads to the upregulation of BMPr1A on the mesenchymal cells that surround them, making these mesenchymal cells responsive to BMP4 that is present within the ventral epidermis. The authors found that as a result of this cooperation between PTHrP and BMP signalling, Msx2 expression is upregulated in the mammary mesenchyme, which then suppresses hair follicle formation in the epithelium immediately surrounding the nipple. In this way, paracrine BMP signalling regulates the fate choice between hair and mammary gland. The authors also propose from their findings that this cooperative PTHrP and BMP signalling enables the mesenchyme to initiate the outgrowth of the mammary epithelial buds. In a separate study focused on later ductal development(), Moraes et al. report on the dysplastic effects that sustained smoothened (Smo)-mediated hedgehog (Hh) signalling has during ductal elongation in virgin transgenic mice. They studied this by expressing activated human SMO (SmoM2) under the control of the mouse mammary tumour virus promoter in transgenic mice. This constitutively active form of Smo induces a pre-cancerous state in the mammary ductal cells of the transgenic mice, in which the increased proliferation of mammary epithelium and differentiation defects are seen, while in vitro, an increased proportion of these cells can undergo anchor-independent growth. From these and other results, the authors put together a model in which Hh signalling must be prevented in the mature ducts of virgin mice, and possibly in the mature ducts of humans as well. Under such a model, ectopic Hh signalling could contribute to early human breast cancer development by stimulating proliferation and by increasing the pool of division-competent cells that are capable of anchorage-independent growth.
