Biological effects and regulation of IGFBP5 in breast cancer

Abstract

The insulin-like growth factor receptor (IGF1R) pathway plays an important role in cancer progression. In breast cancer, the IGF1R pathway is linked to estrogen-dependent signaling. Regulation of IGF1R activity is complex and involves the actions of its ligands IGF1 and IGF2 and those of IGF-binding proteins (IGFBPs). Six IGFBPs are known that share the ability to form complexes with the IGFs, by which they control the bioavailability of these ligands. Besides, each of the IGFBPs have specific features. In this review, the focus lies on the biological effects and regulation of IGFBP5 in breast cancer. In breast cancer, estrogen is a critical regulator of IGFBP5 transcription. It exerts its effect through an intergenic enhancer loop that is part of the chromosomal breast cancer susceptibility region 2q35. The biological effects of IGFBP5 depend upon the cellular context. By inhibiting or promoting IGF1R signaling, IGFBP5 can either act as a tumor suppressor or promoter. Additionally, IGFBP5 possesses IGF-independent activities, which contribute to the complexity by which IGFBP5 interferes with cancer cell behavior.

Keywords: breast cancer; breast cancer susceptibility region; estrogen; insulin-like growth factor binding protein 5; transcriptional regulation.

Figure 1

Structure of the human mature IGFBP5 protein. Three major domains, the N-terminal (N), the linker (L) and the C-terminal (C) domain, can be distinguished, which fulfill different functions as indicated. For high affinity IGF binding, the C-terminal domain is required in addition to the primary IGF binding site (IB) within the N-terminal domain between aa 68 and 74. A nuclear localization signal (NLS) is located within the C-terminal domain between aa 201 and 218, which also mediates binding of the IGFBP5 protein to heparin.

Figure 2

IGFBP5 actions. (A, B) By forming an inhibitory complex with IGF, IGFBP5 can prevent IGF-induced activation of IGF1R at appropriate IGFBP5/IGF ratios. (C) IGF-bound IGFBP5 has also been suggested to function as an IGF storage complex. Sudden release of IGF due to IGFBP5 proteolysis can strongly increase the local IGF concentration, potentially enhancing the IGF effect on IGF1R. In this scenario, IGFBP5 acts as a promoter of IGF activity. (D, E) IGF-independent effects of IGFBP5 either caused by its interaction with a putative plasma membrane receptor (D) or caused by its ability to enter the cell and accumulate in the nucleus (E).

Figure 3

IGFBP5 modulates drug responses of BC cells. IGFBP5 counteracts resistance to the anti-estrogens FULV and TAM by either inhibiting the expression of Bcl-3 or by preventing phosphorylation of ERα at S118, respectively. On the other hand, IGFBP5 de-sensitizes cells to the PI3K inhibitor (i) GDC-0941, involving ERK1/2 activation and downregulation of pro-apoptotic Bim, and to the dual IGF1R/IR inhibitor BMS-536924 through a not yet defined mechanism.

Figure 4

Summary of known factors regulating IGFBP5 expression. Besides proteins that regulate IGFBP5 transcription, namely transcription factors (TFs) (see also Figure 5 ) and chromatin modifiers (CM), other factors have been identified that interfere with IGFBP5 expression. These include other proteins (Wnt, DOG1, Gankyrin), steroids and non-coding RNAs (ncRNAs), namely microRNAs (miRs) and long noncoding RNAs (lncRNAs). Factors that stimulate IGFBP5 expression are denoted in green, those which have a negative effect are shown in red. Factors, which can have either effect dependent on the cellular context, are bicolored.

Figure 5

Overview of chromosome 2q regions relevant to the transcriptional regulation of the human IGFBP5 gene. These regions include the proximal IGFBP5 promoter, several enhancer elements in the protein-coding gene desert 2q35 and an HIF1α-binding downstream regulatory element. Numbers above or below the horizontal line indicate the genomic positions or the nucleotide positions relative to the transcriptional start site (+1) of the IGFBP5 gene, respectively. Green ovals indicate stimulatory transcription factors, red ones repressors. The relative position of the gene DIRC3, whose RNA product interferes with MITF and Sox10 activities, and the SNP site rs4442975, which interferes with FoxA1 binding activity, are indicated. In the lower panel, the transcription factor configuration in the deletion variant esv3594306 and its consequences for the estrogen (E2) response, as measured by promoter reporter or by allele-specific expression assays, are shown. PRE, putative regulatory element.