TGF-beta 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.

Figure 1.

Schematic of the essential regulation of TGF-β production as a latent complex. The small latent complex is composed of a homodimer of the pre-pro peptide, which is designated as latency associated protein, that is noncovalently bound to TGF-β proper, which is a 24-kDa homodimer; this complex can also form the large latent complex on covalently binding the latent TGF-β binding proteins (LTBP). LAP contains the signal sequence for secretion into the extracellular space, which sequesters the latent complex until activation. Activation occurs by multiple mechanisms, that are relatively understudied, to release TGF-β for binding to its receptors, type I, II, and III, that then initiates the signaling cascade.

Figure 2.

Major features of TGF-β biology in the normal mammary gland versus breast cancer. (A) Mammary epithelial cells are exquisitely sensitive to TGF-β, whose activation is highly regulated in normal tissue. During mammary gland development, stromal TGF-β is an essential inhibitor of proliferation and morphogenesis and in the adult tissue epithelial TGF-β regulates the response to ovarian hormones. Notably mammary epithelial cells that contain estrogen receptor (ER) mediate a paracrine signal for proliferation of ER-negative cells and TGF-β acts to specifically restrict proliferation of both cell types. (B) Most breast cancer cells are no longer responsive to the cytostatic action of TGF-β. Aberrant production and activation of TGF-β by invasive breast cancer frequently results in desmoplastic stroma consisting of myofibroblasts and active extracellular matrix remodeling. TGF-β can also drive the acquisition of invasive behaviors in cancer cells undergoing an epithelial-mesenchymal type transition (EMT). Complex biology of angiogenesis and vasculogenesis in tumors is mediated by TGFβ regulation of chemokine expression resulting in the recruitment of myeloid derived suppressor cells (MDSC).