Although the exact mechanisms are not fully understood IGF
Although the exact mechanisms are not fully understood, IGF-1 is tightly linked with ER and estrogen actions and a crosstalk occurs between these two systems in breast cancer. To illustrate this close relationship, studies have identified a synergy between IGF-1 and estrogen in SYR-322 synthesis expressing both IGF-1R and ER. Authors have shown that IGF-1 directly increased the transcriptional activity of the ER in breast cancer cells and increased expression of estrogen-inducible genes, such as the progesterone receptor gene (Lee et al., 1997). Further, blockade of ER function can inhibit IGF-1-mediated mitogenesis and blocking IGF-1 action can inhibit estrogen stimulation of breast cancer cells, suggesting that IGF-1 is partially responsible for estrogen-mediated signaling (Figueroa et al., 1993). As a consequence of this reciprocal crosstalk between ER and IGF-1R, IGF-1 may allow the escape of ER-positive breast tumors from anti-estrogen treatment and patients are likely to develop resistance to endocrine therapy through aberrant upregulation of IGF-1 signaling (Song et al., 2010). Therefore, combination therapies targeting ER and tyrosine kinase receptors may benefit patients with endocrine therapy-resistant breast cancer (Liu et al, 2014, Fox et al, 2013). IGF-1 may interact with estrogen signaling at multiple levels and in multiple fashions. In relation to aromatase regulation, both insulin and IGF-1 have been shown to potentiate the dexamethasone/serum-induced activity of aromatase in breast adipose stromal cells, likely due to activation of aromatase promoter I.4 (Lueprasitsakul et al., 1990, Schmidt and Loffler, 1994). A study conducted by Su and colleagues showed that IGF-1 may increase aromatase activity, in a dose-dependent manner via posttranslational mechanisms, in two breast cancer cell lines transfected with aromatase (Su et al., 2011). In addition to modifications in aromatase regulation and subsequent estrogen production, IGF-1 is also able to induce ER activation without any estrogen binding. While the majority of ER signaling occurs via estradiol binding, estrogen-independent mechanisms have been shown to contribute to ER activation via phosphorylation of the receptor (Stellato et al., 2016). MAPK and PI3K/Akt signaling pathways, both activated by IGF-1, have been shown to phosphorylate the ER at serine 118 and serine 167, leading to ER activation and induction of its transcriptional activity (Le Romancer et al., 2011). Moreover, IGF-1R appears to be essential for the non-genomic, membrane-associated ER activity (Song et al., 2010). Elevated circulating IGF-1 levels found in obese postmenopausal women facilitate interactions between IGF-1R and the membrane-associated ER and enhance non-genomic actions of ER, such as the activation of PI3K/Akt/mammalian target of rapamycin (mTOR) pathway, leading to abnormal regulation of cell cycle or apoptotic signaling (Bowers et al, 2013, Osborne and Schiff, 2011). Increased activation of mTOR is commonly observed in obese mice and mTOR inhibitors block the tumorigenic effects of obesity in mouse models (Moore et al, 2008, De Angel et al, 2013). As a result, IGF-1 acts as a powerful mitogenic factor in hormone-dependent breast cancer cells by supporting and enhancing estrogen/ER-promoted growth in obese patients. Importantly, a recent observational study comparing White and African American postmenopausal women mentions that bioavailable IGF-1 is potentially important in racial disparities in obesity-related breast cancer risk (Jung et al., 2017). Hyperinsulinemia, another characteristic feature of obesity and metabolic syndrome, has been shown to be associated with increases in free IGF-1 levels in obese patients by downregulating IGF binding protein production and by promoting hepatic growth factor receptor and IGF-1 synthesis (Arcidiacono et al., 2012). Insulin is also an important modulator of estrogen concentrations since hyperinsulinemia has been associated with reduced serum SHBG levels, leading to increased bioavailable estrogens (Gascon et al., 2000). Moreover, insulin influences breast cancer risk and progression by its significant role as a growth factor. Numerous experiments have reported that insulin promoted proliferation, migration and invasion of ER-positive breast cancer cell lines (Milazzo et al, 1992, Ogasawara and Sirbasku, 1988). Moreover, chronic hyperinsulinemia increases breast cancer growth through ER activation and modulation of cell cycle and apoptotic factors (Wairagu et al., 2015). For these reasons, type 2 diabetes which is associated with high plasma insulin concentrations has also been linked to an increased risk of developing postmenopausal breast cancer, independently of any coexisting obesity. A meta-analysis of 20 studies from nine different countries showed a 20% increase in breast cancer risk in women with diabetes compared with nondiabetics, with adjustment for BMI having no significant effect on this result (Rose and Vona-Davis, 2012, Larsson et al., 2007). These data suggest that exposure to insulin and factors associated with metabolic dysfunction, rather than BMI per se is the important etiologic factor and is associated with an increased risk of postmenopausal hormone-dependent breast cancer (Rose et al., 2015).