First published online March 1, 2007
Development 134, 604e (2007)
© The Company of Biologists Limited
Mammary development: from normal to pathological
How the mammary gland develops from buds in the ventral embryonic epidermis
and how subsequent ducts develop are poorly understood. Now Hens et al.
(p. 1221) 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
(p. 1231), 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.
Related articles in Development:
- BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction
- Julie R. Hens, Pamela Dann, Jian-Ping Zhang, Stephen Harris, Gertraud W. Robinson, and John Wysolmerski
Development 2007 134: 1221-1230.
[Abstract]
[Full Text]
- Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia
- Ricardo C. Moraes, Xiaomei Zhang, Nikesha Harrington, Jennifer Y. Fung, Meng-Fen Wu, Susan G. Hilsenbeck, D. Craig Allred, and Michael T. Lewis
Development 2007 134: 1231-1242.
[Abstract]
[Full Text]
