Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers

Abstract

To date, almost all solid malignancies have implicated insulin-like growth factor (IGF) signalling as a driver of tumour growth. However, the remarkable level of crosstalk between sex hormones, the IGF-1 receptor (IGF-1R) and its ligands IGF-1 and 2 in endocrine driven cancers is incompletely understood. Similar to the sex steroids, IGF signalling is essential in normal development as well as growth and tissue homoeostasis, and undergoes a steady decline with advancing age and increasing visceral adiposity. Interestingly, IGF-1 has been found to play a compensatory role for both estrogen receptor (ER) and androgen receptor (AR) by augmenting hormonal responses in the absence of, or where low levels of ligand are present. Furthermore, experimental, and epidemiological evidence supports a role for dysregulated IGF signalling in breast and prostate cancers. Insulin-like growth factor binding protein (IGFBP) molecules can regulate the bioavailability of IGF-1 and are frequently expressed in these hormonally regulated tissues. The link between age-related disease and the role of IGF-1 in the process of ageing and longevity has gained much attention over the last few decades, spurring the development of numerous IGF targeted therapies that have, to date, failed to deliver on their therapeutic potential. This review will provide an overview of the sexually dimorphic nature of IGF signalling in humans and how this is impacted by the reduction in sex steroids in mid-life. It will also explore the latest links with metabolic syndromes, hormonal imbalances associated with ageing and targeting of IGF signalling in endocrine-related tumour growth with an emphasis on post-menopausal breast cancer and the impact of the steroidal milieu.

SRSF‐1 and microvessel density immunohistochemical analysis by semi‐automated tissue microarray in prostate cancer patients with diabetes (DIAMOND study)

“…22 These results in fact show how there is a synergy of functionality between the androgen receptor and IGF-1. 23 In PC cell lines, insulin and IGF-1 increase cell proliferation and glucose uptake while IR-β is not associated with cancer cell proliferation but it induces differentiation in noncancerous prostate cells. However, IGF-1R and IR-α overexpression enhances angiogenesis and proliferation.…”

“… 22 These results in fact show how there is a synergy of functionality between the androgen receptor and IGF‐1. 23 …”

“…Pandini and colleagues in 2005, however, highlighted how androgens in PC cells are able to over‐regulate the expression of the IGF‐1 receptor and as a consequence in determining an increase in the same proliferation and invasion when stimulated with IGF‐1 22 . These results in fact show how there is a synergy of functionality between the androgen receptor and IGF‐1 23 …”

Staphylococcus aureus-Derived Extracellular Vesicles Enhance the Efficacy of Endocrine Therapy in Breast Cancer Cells

“…It is abundant in elderly, healthy controls but almost absent in breast cancer patients ( Figure 3 ). After estrogen treatment in a previous study, there was an interaction between the estrogen receptor (ER) and insulin−like growth factor (IGF) receptor [ 36 ]. Phosphorylation of ERK is required for the binding of ER to the IGF−1 receptor [ 37 ].…”

Hepatocrinology

“…Notable among them is the development of hormone-sensitive cancers. There is emerging evidence that cross-talk between sex steroids and IGF-1 modulates the propensity for the development of breast and prostate cancers [ 23 , 24 ]. The various pathophysiological effects of the GH-IGF-1 axis are thus orchestrated through IGF and IGFBP synthesized in the liver.…”