Transforming growth factor-beta and breast cancer: Lessons learned from genetically altered mouse models

Abstract

Transforming growth factor (TGF)-betas are plausible candidate tumor suppressors in the breast. They also have oncogenic activities under certain circumstances, however. Genetically altered mouse models provide powerful tools to analyze the complexities of TGF-beta action in the context of the whole animal. Overexpression of TGF-beta can suppress tumorigenesis in the mammary gland, raising the possibility that use of pharmacologic agents to enhance TGF-beta function locally might be an effective method for the chemoprevention of breast cancer. Conversely, loss of TGF-beta response increases spontaneous and induced tumorigenesis in the mammary gland. This confirms that endogenous TGF-betas have tumor suppressor activity in the mammary gland, and suggests that the loss of TGF-beta receptors seen in some human breast hyperplasias may play a causal role in tumor development.

Figure 1

Transforming growth factor (TGF)-β has tumor suppressor and oncogenic activities. Acting directly on the mammary epithelium, TGF-β could suppress tumorigenesis through a number of mechanisms, including inhibition of epithelial cell proliferation, induction of apoptosis or senescence in initiated cells, and maintenance of genomic stability. All of these activities require an intact epithelial response to TGF-β. TGF-β can also have pro-oncogenic effects. These may be either direct, or indirect via the stroma. Direct effects include the promotion of the epithelial-mesenchymal transition and invasiveness, and an increase in production of parathyroid hormone-related peptide (PTHrP). These are also dependent on an intact epithelial response system. Indirect effects include the induction of angiogenesis, and suppression of the immune surveillance system. The indirect oncogenic effects are presumed to dominate when epithelial responsiveness to TGF-β is lost.

Figure 2

Transforming growth factor (TGF)-β has direct and indirect effects on morphogenesis and function of the mammary epithelium. TGF-β acts directly on the epithelium to prevent precocious alveolar development and milk protein production in virgin mice. Acting indirectly, via the stroma, it may inhibit ductal branching, possibly through effects on activity of the morphogen hepatocyte growth factor.