Role of TGF-β and the tumor microenvironment during mammary tumorigenesis

Abstract

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that functions to inhibit mammary tumorigenesis by directly inducing mammary epithelial cells (MECs) to undergo cell cycle arrest or apoptosis, and to secrete a variety of cytokines, growth factors, and extracellular matrix proteins that maintain cell and tissue homeostasis. Genetic and epigenetic events that transpire during mammary tumorigenesis typically inactivate the tumor suppressing activities of TGF-beta and ultimately confer this cytokine with tumor promoting activities, including the ability to stimulate breast cancer invasion, metastasis, angiogenesis, and evasion from the immune system. This dramatic conversion in TGF-beta function is known as the "TGF-beta paradox" and reflects a variety of dynamic alterations that occur not only within the developing mammary carcinoma, but also within the cellular and structural composition of its accompanying tumor microenvironment. Recent studies have begun to elucidate the critical importance of mammary tumor microenvironments in manifesting the TGF-beta paradox and influencing the response of developing mammary carcinomas to TGF-beta. Here we highlight recent findings demonstrating the essential function of tumor microenvironments in regulating the oncogenic activities of TGF-beta and its stimulation of metastatic progression during mammary tumorigenesis.

Figure 1

TGF-β is a master regulator of MEC plasticity and microenvironmental homeostasis. TGF-β induces malignant MECs to undergo EMT, leading to the acquisition of highly migratory, invasive, and metastatic phenotypes. TGF-β is also a potent inducer of tumor angiogenesis, which significantly enhances the growth and metastasis of late-stage mammary tumors. Through its ability to inhibit host immunosurveillance, TGF-β also plays an essential role in conferring immune privilege to developing and progressing breast cancers. Finally, TGF-β stimulates fibroblasts to synthesize and secret a variety of growth factors, cytokines, and ECM molecules that collectively create a tumor promoting microenvironment.

Figure 2

Schematic of canonical TGF-β signaling within distinct cell types located in tumor microenvironments. TGF-β predominantly activates a Smad2/3-based pathway in fibroblasts, epithelial, and immune cells (left panel), and in endothelial cells subjected to high TGF-β concentrations (right panel). In contrast, endothelial cells subjected to low TGF-β concentrations activate a Smad1/5/8-based pathway (middle panel). In general, TGF-β in the extracellular space binds either to TβR-III or endoglin, both of which present TGF-β to TβR-II. In some cells, TGF-β can bind directly to TβR-II independent of TβR-III or endoglin expression on the cell membrane. TβR-II bound to TGF-β then recruits, transphosphorylates, and activates the TβR-I isozymes, ALK-5 and ALK-1. Activated TβR-I/ALK-5 or TβR-I/ALK-1 then phosphorylate and activate Smad2/3 or Smad1/5/8, respectively, which then form heteromeric complexes with Smad4 that readily accumulate in the nucleus to regulate changes in gene expression in a cell- and context-specific manner.