The role of the insulin-like growth factor-1 system in breast cancer

Abstract

IGF-1 is a potent mitogen of major importance in the mammary gland. IGF-1 binding to the cognate receptor, IGF-1R, triggers a signaling cascade leading to proliferative and anti-apoptotic events. Although many of the relevant molecular pathways and intracellular cascades remain to be elucidated, a growing body of evidence points to the important role of the IGF-1 system in breast cancer development, progression and metastasis. IGF-1 is a point of convergence for major signaling pathways implicated in breast cancer growth. In this review, we provide an overview and concise update on the function and regulation of IGF-1 as well as the role it plays in breast malignancies.

Figure 1

The IGF-1 role in breast cancer. IGF-1 is mostly secreted by stromal cells and acts through paracrine signaling to adjacent epithelial tumor cells and vice versa. Once the disease is well established within the primary breast tumor microenvironment, IGF-1 autocrine (within epithelium) and endocrine (via the systemic circulation) activity facilitates disease progression and metastasis respectively. Within the new tumor location, the interplay between metastasized breast cancer cells and host tissue cells, drive the last to a more cancerous phenotype via IGF-1 paracrine signaling. In addition, aberrant IGF-1 expression by host tissue cells supports BrCa proliferation via autocrine signaling.

Figure 2

The IGF-1 receptor (auto-) regulation mechanism in breast cancer. SUMOylation of the IGF-1 receptor drives IGF-1R to nuclear translocation. Nuclear IGF-1R upregulates IGF-1R protein levels through direct binding to its own promoter. Other factors could also contribute to IGF-1R transcriptional regulation acting both as enhancers (ERα, miR515-5p and transcription factors c-Jun, Sp1, KLF6, E2F1,) or inhibitors (IGF-1, BRCA1, PARP, tumor suppressors p53, VHL, and transcription factor WT1). SUMO: small ubiquitin-like modifier; ERα: Estrogen receptor α; BRCA1: Breast cancer 1-early onset protein; KLF6: Kruppel-like factor 6; PARP: Poly-ADP ribose polymerase; VHL: von Hippel Lindau protein; WT1: Wilms tumor 1 protein.

Figure 3

Schematic representation of the crosstalk between the IGF-1 system and estrogens in breast cancer. Binding of IGF-1 to IGF-1R triggers both PI3K/AKT/mTOR and MAPK/ERK signaling pathways, leading to enhanced breast cancer growth and proliferation. S6K1, a downstream molecule of the AKT/mTOR pathway induces phosphorylation of ERα. Activated ERα acts as transcription factor, through direct binding to promoter of target genes, consequently upregulating IGF-1, IGF-1R and other ERα-induced genes which also stimulate breast cancer progression. Prostaglandin E2 (PGE2) along with HER2 and both phosphorylated AKT and MAPK enhance aromatase activity through post-transcriptional mechanisms leading to elevated estrogen levels. Estrogens further contribute to transcriptional regulation of both IGF-1 and IGF-1R, consequently recycling the system’s signaling, enhancing growth and proliferation of breast tumors. S6K1: Ribosomal protein S6 kinase 1 protein; mTOR: mammalian target of rapamycin; HER2: human epidermal growth factor receptor 2 protein.