TGF-β Biology in Mammary Development and Breast Cancer
Abstract
Transforming growth factor-β1 (TGF-β) was first implicated in mammary epithelial development by Daniel and Silberstein in 1987 and in breast cancer cells and hormone resistance by Lippman and colleagues in 1988. TGF-β is critically important for mammary morphogenesis and secretory function through specific regulation of epithelial proliferation, apoptosis, and extracellular matrix. Differential TGF-β effects on distinct cell types are compounded by regulation at multiple levels and the influence of context on cellular responses. Studies using controlled expression and conditional-deletion mouse models underscore the complexity of TGF-β biology across the cycle of mammary development and differentiation. Early loss of TGF-β growth regulation in breast cancer evolves into fundamental deregulation that mediates cell interactions and phenotypes driving invasive disease. Two outstanding issues are to understand the mechanisms of biological control in situ and the circumstances by which TGF-β regulation is subverted in neoplastic progression.
The discovery of a “transforming growth factor” in normal tissue and serum in the early 1980s rapidly led to the identification of a large family of polypeptides whose action is involved in all aspects of development, homeostasis, and cancer (Moses and Roberts 2008). The activity of transforming growth factor-β1 (TGF-β) was first implicated in mammary epithelial development in 1987 by a canonical experiment by Daniel and Silberstein. Pellets containing TGF-β implanted into mouse mammary gland during ductal morphogenesis were shown to induce rapid regression of advancing endbuds, which was among the first demonstration of its potent inhibitory, rather than transforming, activity (Silberstein and Daniel 1987). However, soon after, Lippman and colleagues showed that TGF-β was produced by breast cancer cells, which in turn contributed to their hormone resistance (Knabbe et al. 1987). These two diametrically opposed actions have continued to fascinate those studying its sundry roles in mammary biology and breast cancer. After nearly a quarter century, this brief article underscores the major two themes in mammary biology: Although TGF-β orchestrates tissue composition and critical controls during mammary development, its subversion during cancer progressively undermines homeostasis and actively drives malignancy.
ACKNOWLEDGMENTS
The authors wish to acknowledge funding for MHBH from the Bay Area Breast Cancer and the Environment Research Center grant number U01 {"type":"entrez-nucleotide","attrs":{"text":"ES012801","term_id":"163973201","term_text":"ES012801"}}ES012801, and from the National Institute of Environmental Health Sciences, National Institutes of Health (NIH), and the National Cancer Institute, NIH.
Footnotes
Editors: Mina J. Bissell, Kornelia Polyak, and Jeffrey Rosen
Additional Perspectives on The Mammary Gland as an Experimental Model available at www.cshperspectives.org