Diversity of insulin and IGF signaling in breast cancer: Implications for therapy
Introduction
A number of comprehensive reviews have been written about the insulin and IGF signaling pathway and its role in cancer (Belfiore et al., 2009; Gallagher and LeRoith, 2020; Pollak, 2008), and especially in breast cancer (Farabaugh et al., 2015), and they have elaborated the pre-clinical evidence to support the involvement of this signaling pathway in both cancer risk and progression. Unfortunately, efforts to inhibit this pathway in the clinic have been unsuccessful to date, in part due to adverse effects of therapies on normal physiology (Pollak, 2012; Yang and Yee, 2012). In this review we will provide an overview of the IR/IGF-1R signaling pathway and its importance for breast cancer and we will highlight the more recent discoveries that provide continued optimism for targeting insulin and IGF signaling for the treatment of breast cancer patients. The lessons learned at the bedside when targeting the IR/IGF-1R pathway need to be brought back to the bench for further basic research. A more rigorous understanding of the molecular mechanisms by which this pathway signals to regulate breast tumor progression is needed to facilitate the development of more selective and effective therapies.
Section snippets
The IR/IGF-1R signaling pathway in normal physiology
Before discussing the IR/IGF-1R signaling pathway in breast cancer, it is necessary to understand the players involved and their role in normal organismal growth and metabolism, because it is the dysregulation of these normal functions that contribute to breast cancer development and progression. In addition, issues that arise in response to targeting this pathway for cancer treatment are related to adverse effects of disrupting these normal functions.
The IR/IGF-1R signaling pathway in breast cancer
IR/IGF-1R pathway function is tightly regulated to maintain normal organismal growth and metabolism. Dysregulation of this pathway leads to pathophysiological conditions including diabetes and cancer. With regard to the latter, aberrant IR/IGF-1R signaling has been implicated in the initiation and progression of many types of cancer, including breast cancer (reviewed in (Gallagher and LeRoith, 2020; Pollak, 2008)). Alterations in expression and function of ligands, receptors and signaling
Targeting the IR/IGF1R signaling pathway in breast cancer
The strong association of the IR/IGF-1R pathway with clinical outcomes in cancer and the extensive pre-clinical data supporting the functional role of this pathway in cancer progression have led to efforts to develop targeted drugs to inhibit this signaling axis in tumors (Fig. 2) (King et al., 2014).
Future directions
The evidence to support an important role for the IR/IGF-1R signaling pathway in breast cancer promotion and progression is compelling. Unfortunately, early excitement about the potential for targeting the IR/IGF-1R signaling axis as a therapeutic approach in breast cancer has been diminished by disappointing results from clinical trials, and many drug programs have been halted. One lesson that has been learned from efforts to target the IGF-1R pathway in cancer is that improved biomarkers that
Authors’ contributions
All of the authors contributed to the preparation and editing of this manuscript. All of the authors have read and approved the final manuscript.
Declaration of competing interest
The authors declare that they have no competing interests.
Acknowledgments
This work was supported by NIH grants CA240655 and CA229910 to LMS. We thank Art Mercurio for helpful comments on the manuscript. The Figures were created using BioRender.com.
References (143)
- et al.
Role of insulin-like growth factors in embryonic and postnatal growth
Cell
(1993) - et al.
Therapeutic implications of cellular heterogeneity and plasticity in breast cancer
Cell Stem Cell
(2015) - et al.
Keeping IGF-II under control: lessons from the IGF-II-IGF2R crystal structure
Trends Biochem. Sci.
(2009) - et al.
Functional significance of type 1 insulin-like growth factor-mediated nuclear translocation of the insulin receptor substrate-1 and beta-catenin
J. Biol. Chem.
(2005) - et al.
Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway
J. Biol. Chem.
(1998) - et al.
Parental imprinting of the mouse insulin-like growth factor II gene
Cell
(1991) - et al.
IGF1R constitutive activation expands luminal progenitors and influences lineage differentiation during breast tumorigenesis
Dev. Biol.
(2020) - et al.
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation
Biochimie
(2005) - et al.
Synergistic proliferative action of insulin-like growth factor I and 17 beta-estradiol in MCF-7S breast tumor cells
Exp. Cell Res.
(2002) - et al.
Hallmarks of cancer: the next generation
Cell
(2011)