The Impact of FGF Expression in Breast Cancer

Fibroblast growth factors (FGFs) are ubiquitous growth factors, with functions in all organs and cells of the embryo and the post-partum mammal, and roles in all aspects of normal and pathologic physiology. They belong to a large family of proteins categorized into seven subfamilies with 23 members. FGF molecules initiate signaling through varied and interacting mechanisms that result in a highly diverse spectrum of multifunctional effects. FGF molecules induce their effects by binding to transmembrane tyrosine kinase receptors to initiate canonical signal transduction pathways, and by internalization of the FGF/FGF receptor (FGFR) complexes and directing intracellular non-canonical signaling in the cytoplasm and the nucleus. FGF proteins expressed by a cell can also engage in non-canonical intracellular signaling in the cytoplasm, in the nucleus, or by undergoing extracellular export and initiating autocrine, receptor-mediated signaling. In the mammalian breast, FGF family members play significant roles in embryonic and postnatal mammary gland development and the normal female mammalian life cycle. In breast cancer (BC), the intracellular detection of FGF family members has been associated with both cancer-promoting and cancer-inhibitory effects. The goal of this review is to deconvolute the often contradictory published data resulting in these differing impacts of FGF expression on BC. Within the context of these variables, there is a potential for an extraordinarily high number of combinatorial interstudy scenarios, interactive variables, experimental designs, and circumstance-specific responses to potential signal-initiating scenarios, rendering generalizations difficult. However, the available evidence suggests that pro-malignant FGF effects in BC are generally mediated by the combined effects of intracellularly initiated signaling and cell membrane FGFR-mediated autocrine or paracrine canonical signaling, together with crosstalk with other external factors. In contrast, the anti-cancer effects of intracellular FGF molecules are primarily mediated by intracellular signaling that results in the redifferentiation of cancer cells and adhesion-mediated crosstalk with the stroma.