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Review
. 2022 Nov 29;12(12):1992.
doi: 10.3390/life12121992.

The Insulin-like Growth Factor Signaling Pathway in Breast Cancer: An Elusive Therapeutic Target

Ji-Sun Lee  1 , Claire E Tocheny  1 , Leslie M Shaw  1
Affiliations
Review

The Insulin-like Growth Factor Signaling Pathway in Breast Cancer: An Elusive Therapeutic Target

Ji-Sun Lee et al. Life (Basel). .

Abstract

In this review, we provide an overview of the role of the insulin-like growth factor (IGF) signaling pathway in breast cancer and discuss its potential as a therapeutic target. The IGF pathway ligands, IGF-1 and IGF-2, and their receptors, primarily IGF-1R, are important for normal mammary gland biology, and dysregulation of their expression and function drives breast cancer risk and progression through activation of downstream signaling effectors, often in a subtype-dependent manner. The IGF signaling pathway has also been implicated in resistance to current therapeutic strategies, including ER and HER2 targeting drugs. Unfortunately, efforts to target IGF signaling for the treatment of breast cancer have been unsuccessful, due to a number of factors, most significantly the adverse effects of disrupting IGF signaling on normal glucose metabolism. We highlight here the recent discoveries that provide enthusiasm for continuing efforts to target IGF signaling for the treatment of breast cancer patients.

Keywords: IGF-1 receptor (IGF-1R); breast cancer; insulin receptor substrate (IRS) proteins; insulin-like growth factor (IGF); signal transduction; therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The insulin and IGF signaling (IIS) axis. The IIS pathway is comprised of ligands (Insulin, IGF-1, IGF-2), receptors (IR: insulin receptor; IGF-1R: IGF-1 receptor, IGF-2R: IGF-2 receptor), and IGF binding proteins (IGFBPs). IR and IGF-1R subunits homodimerize or heterodimerize to mediate downstream signaling through SHC and insulin receptor substrate (IRS) proteins. The IGF-2R serves as a decoy receptor to inhibit IGF-2 mediated signaling. Under normal physiologic conditions, insulin preferentially binds to the IRs, IGF-1 binds to the IGF-1R and IR/IGF-1R hybrid receptors, and IGF-2 binds to the IR-A, IGF-1R, and IR-A/IGF-1R hybrid receptors. IGFBPs control bioavailability of IGF-1 or IGF-2.
Figure 2
Figure 2
Functions of the IGF signaling pathway in breast cancer. IGF signaling is implicated at many stages of the multi-step process of breast cancer initiation and progression including: breast tumor initiation and cancer stem cell (CSC) regulation (A,B); primary tumor growth through the enhancement of proliferation and inhibition of apoptosis (C); promotion of neovascularization(angiogenesis) and lymphangiogenesis to facilitate tumor growth and dissemination (D); induction of epithelial-to mesenchymal transition (EMT) to enable tumor cell migration and invasion into the local tumor microenvironment (E,F); and metastatic colonization of secondary tissues (G). Hyperactive IGF signaling also confers resistance to a broad range of therapeutics (H).
Figure 3
Figure 3
Therapeutics targeting the IGF signaling pathway. Anti-IGF-1R monoclonal antibodies block interaction between IGF-1R and the IGF ligands and induce internalization and degradation of surface receptors. Small molecule IGF-1R/IR receptor tyrosine kinase inhibitors (RTKi) block kinase activity to disrupt signaling. IGF neutralizing antibodies directly target IGF-1 and IGF-2 to prevent their interaction with receptors. Fasting mimicking diet (FMD) lowers basal glucose levels and suppresses IGF-1/IGF-2 expression and bioavailability. In doing so, FMD enhances the efficacy of chemotherapy.
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