Role of the IGF-1 Axis in Overcoming Resistance in Breast Cancer

Abstract

Over the last two decades, many studies have demonstrated that the insulin-like growth factor-1 (IGF-1) is involved in a number of patho-physiological processes, as well as in the development of different types of solid tumors, including breast cancer (BC). Preclinical and clinical data showed that IGF-1 receptor (R) is overexpressed and hyper-phosphorylated in several subtypes of BCs. The central implications of this pathway in tumor cell proliferation and metastasis make it an important therapeutic target. Moreover, the IGF-1 axis has shown strong interconnection with estrogen regulation and endocrine therapy, suggesting a possible solution to anti-estrogen resistance. IGF-1R might also interfere with other pivotal therapeutic strategies, such as anti HER2 treatments and mTOR inhibitors; several clinical trials are ongoing evaluating the role of IGF-1R inhibition in modulating resistance mechanisms to target therapies. Our aim is to offer an overview of the most recent and significant field of application of IGF-1 inhibitors and relevant therapeutic strategies, weighing their possible future impact on clinical practice.

Invasion and Metastasis as a Central Hallmark of Breast Cancer

“…Moreover, up-regulation of IGF1R is used by breast cancer cells as a mechanism of resistance to HER2, EGFR and anti-estrogen inhibitors. These mechanisms suggest combining IGF1R inhibitors with other targeted therapies as an effective therapeutic strategy [20,23].…”

The pleiotropic roles of adipocyte secretome in remodeling breast cancer

“…Tumor stroma-derived insulin-like growth factor 1(IGF-1) and insulin-like growth factor binding protein (IGFBP) signaling have the potential to be novel targets for cancer therapy or adjuvant treatment, but these therapies have so far failed to yield significant efficacy [ 48 ]. IGFBPs show a tendency to be overexpressed and phosphorylated in several breast cancer subtypes, resulting in cancer cell proliferation, metastasis, and drug resistance-related properties [ 49 ]. The expression of IGF-1 content, which was regulated by glucose and fatty acids, was observably up-regulated in undifferentiated cells and differentiated adipocytes from obese individuals than those from lean individuals [ 50 ].…”

IGF Signaling in Intervertebral Disc Health and Disease

“…The IGF axis is composed of ligands such as insulin, insulin-like growth factors 1 and 2 (IGF1, IGF2), receptors (IGF-1R, IGF-2R), IGF binding proteins (IGFBPs) one to seven, and IGFBP protease (Martel-Pelletier et al, 1998;Wang et al, 2014;Hua et al, 2020;Ianza et al, 2021). IGF ligands bind its receptors and binding proteins with high affinity (Huang et al, 2011a;Okamoto et al, 2013).…”

“…The function of IGFBPs is to bind to IGF, extend the circulating half-life, and prevent the activation of IGF receptors (Patel and Majumdar, 2009;Kobayashi-Hattori et al, 2011). IGFBP protease cleaves IGFBP into fragments with a lower affinity for IGF ligands, thereby improving the bioavailability of free IGF (Peters et al, 2003;Ianza et al, 2021). Three main proteases can cleave IGFBP, including serine proteases, cathepsins, and matrix metalloproteinases (MMPs) (Grimberg and Cohen, 2000;Garcia-Touchard et al, 2005;Chao et al, 2021).…”