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Despite these conflicting data about COX ER correlations
Despite these conflicting data about COX-2/ER correlations, a large body of evidence supports that elevated COX-2 expression in breast cancer is a constant feature of high stage disease and a predictor of worse outcome. Upregulation of COX-2 protein has been identified in approximately 40% of cases of human invasive breast carcinomas and has been correlated with aggressiveness parameters such as high grade, large tumor size or HER-2 overexpression (Ristimaki et al., 2002). Animal experiments provide further data suggesting that COX-2 overexpression can promote breast carcinogenesis. Transgenic COX-2 overexpression drives mammary tumor formation, and, conversely, knocking out COX-2 reduces tumor formation in rodent models of breast cancer. Liu et al. demonstrated that overexpression of the human gene COX-2 in the mammary gland of transgenic mice is sufficient to induce tumorigenic transformation by decreasing the apoptotic index of mammary epithelial am580 mg (Liu et al., 2001).
Elevated levels of PGE2 have been associated with the obese condition (Bowers et al, 2015, Fain et al, 2002). In addition to the presence of a higher number of macrophages, several parameters linked to obesity may also be responsible for an increase in PGE2 production in obese patients. Nutrient excess such as saturated free fatty acids that are elevated in obesity stimulate COX-2 induction and subsequent PGE2 production by macrophages (Hellmann et al., 2013). If the connection between COX-2 and obesity-induced breast cancer can be attributed to the direct effects of PGE2 on breast epithelial cell apoptosis, migration, invasion and possibly proliferation (Liu et al, 2001, Basu et al, 2005, Singh et al, 2005, Singh et al, 2007), PGE2 is also a potent stimulator of pre-adipocyte aromatase expression and subsequent estrogen production (Bowers and deGraffenried, 2015, Zhou et al, 2005). Consistently, a strong positive correlation between COX-2 and aromatase expression in human breast carcinomas has been observed by immunochemistry in several histological studies (Brodie et al, 2001, Brueggemeier et al, 1999).
PGE2 binds to E prostanoid (EP) receptors which are G protein-coupled receptors with seven transmembrane domains and subdivided into four types termed EP1 through EP4 (Sugimoto and Narumiya, 2007). They are able to modulate Ca2+, cyclic AMP (cAMP) and inositol phosphate intracellular levels, affecting downstream signaling pathways. In obesity-related inflammation, it has been shown that the PGE2/cAMP/protein kinase A (PKA) signaling pathway results in the stimulation of promoters I.3/PII and subsequent increase in aromatase expression and estrogen production (Morris et al, 2011, Howe et al, 2013). Recent work has helped to define signaling mediators and direct downstream effectors of PGE2 implicated in promoter I.3/PII-derived transcripts which include CREB, CRTCs, HIF-1α, LRH-1, MAPK, LKB1 and PKM2, described in the following paragraphs.
IGF-1/IGF-1R/insulin system and estrogen signaling: a critical interplay
Hyperinsulinemia and dysregulation of growth factor signaling pathways, particularly insulin-like growth factor-1 (IGF-1) signaling, can contribute to breast carcinogenesis. They can be the source of dysregulated metabolic pathways observed in obesity and interfere with estrogen signaling in the breast. Obesity is typically accompanied by a higher bioavailability of IGF-1, considered the more relevant obesity-related growth factor (Nam et al, 1997, Frystyk et al, 1995, D'Esposito et al., 2012). IGF-1 is a peptide hormone produced primarily by hepatocytes following stimulation by growth hormone (Philippou et al., 2014). IGF-1, by binding to the transmembrane tyrosine kinase IGF-1 receptor (IGF-1R), regulates key biological processes such as proliferation, differentiation and development of many tissues, particularly during embryonic development (Agrogiannis et al., 2014). IGF-1 is found in the majority of human tissues, including mammary glands, where it is a key mediator of mammary terminal end bud and ductal formation (Ruan and Kleinberg, 1999). Not surprisingly, the IGF-1/IGF-1R system has been reported to play a role in the development of many cancer types, including breast cancer, by affecting cell proliferation, migration and metastasis formation (D'Esposito et al., 2012, Pollak, 2012, Morimura and Takahashi, 2011). IGF-1R is frequently overexpressed in breast cancer and several studies have indicated a positive correlation between IGF-1R expression and disease development and progression (Papa et al, 1993, Jones et al, 2007). Ligand binding and subsequent phosphorylation of IGF-1R triggers the downstream activation of two major signal transduction cascades; the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathways (Denduluri et al., 2015). In turn, activated MAPK and PI3K/Akt pathways alter the expression of genes involved in cell cycle progression and cell death prevention, respectively (Zha and Lackner, 2010, Kennedy et al, 1997). Microarray analysis in an ex vivo model of primary breast fibroblasts revealed a signature of genes associated with proliferation following stimulation with IGF-1, suggesting that IGF-1 has an impact not only on cancer cells themselves but also on stromal adipose cells (Rajski et al., 2010).