ABSTRACT
Epigenetics refers to heritable changes in gene expression that are independent of alterations in DNA sequence. It is now accepted that disruption of epigenetic mechanisms plays a key role in the pathogenesis of cancer: culminating in altered gene function and malignant cellular transformation. DNA methylation and histone modifications are the most widely studied changes but non-coding RNAs such as miRNAs are also considered part of the epigenetic machinery. The insulin-like growth factor (IGF) axis is composed of two ligands, IGF-I and -II, their receptors and six high affinity IGF binding proteins (IGFBPs). The IGF axis plays a key role in cancer development and progression. As IGFBP genes have consistently been identified among the most common to be aberrantly altered in tumours, this review will focus on epigenetic regulation of IGFBP-3 in cancer for which the majority of evidence has been obtained.
ABSTRACT
Evidence indicates that for most human cancers the problem is not that gene mutations occur but is more dependent upon how the body deals with damaged cells. It has been estimated that only about 1% of human cancers can be accounted for by unmistakable hereditary cancer syndromes, only up to 5% can be accounted for due to high-penetrance, single-gene mutations, and in total only 5%-15% of all cancers may have a major genetic component. The predominant contribution to the causation of most sporadic cancers is considered to be environmental factors contributing between 58% and 82% toward different cancers. A nutritionally poor lifestyle is associated with increased risk of many cancers, including those of the breast. As nutrition, energy balance, macronutrient composition of the diet, and physical activity levels are major determinants of insulin-like growth factor (IGF-I) bioactivity, it has been proposed that, at least in part, these increases in cancer risk and progression may be mediated by alterations in the IGF axis, related to nutritional lifestyle. Localized breast cancer is a manageable disease, and death from breast cancer predominantly occurs due to the development of metastatic disease as treatment becomes more complicated with poorer outcomes. In recent years, epithelial-to-mesenchymal transition has emerged as an important contributor to breast cancer progression and malignant transformation resulting in tumor cells with increased potential for migration and invasion. Furthermore, accumulating evidence suggests a strong link between components of the IGF pathway, epithelial-to-mesenchymal transition, and breast cancer mortality. Here, we highlight some recent studies highlighting the relationship between IGFs, IGF-binding protein 3, and epithelial-to-mesenchymal transition.
ABSTRACT
Recent evidence from epidemiology indicates that inter-individual variations in the growth hormone (GH)/IGF-I pathway affect the risk of individuals developing common epithelial cancers. This is supported by associations between normal common variants within genes from the pathway and these cancers, which excludes many potential confounding issues, such as reverse causality. This raises concern for the increasing numbers of patients treated with GH; although replacement therapy for GH-deficiency should aim to restore normality, which should then only incur a normal risk. The links with cancer also offers promising new opportunities. Clinical trials treating cancer patients with pharmaceuticals targeting the IGF-I receptor are well advanced with promising initial findings. In the future, there has to be much more emphasis within oncology on prevention and the GH/IGF-I pathway is one of few identified risk factors that are modifiable, not just by pharmaceutical, but also nutritional, interventions that may, in the long term, be more appropriate. Assessing the status of the GH/IGF-I pathway in individuals may also provide a means for targeting screening programs and preventative measures.
