Diversity of insulin and IGF signaling in breast cancer: Implications for therapy

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Abstract

This review highlights the significance of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway in cancer and assesses its potential as a therapeutic target. Our emphasis is on breast cancer, but this pathway is central to the behavior of many cancers. An understanding of how IR/IGF-1R signaling contributes to the function of the normal mammary gland provides a foundation for understanding its aberrations in breast cancer. Specifically, dysregulation of the expression and function of ligands (insulin, IGF-1 and IGF-2), receptors and their downstream signaling effectors drive breast cancer initiation and progression, often in a subtype-dependent manner. Efforts to target this pathway for the treatment of cancer have been hindered by several factors including a lack of biomarkers to select patients that could respond to targeted therapy and adverse effects on normal metabolism. To this end, we discuss ongoing efforts aimed at overcoming such obstacles.

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.

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