Secondly leptin has been shown

Secondly, leptin has been shown to enhance aromatase mRNA expression, aromatase content and its enzymatic activity in epithelial breast cancer PF 4800567 hydrochloride by inducing promoters II and I.3 via an enhanced binding of transcription activator protein 1 (AP-1) complex to specific DNA sites in the promoter region (Catalano et al., 2003). This leptin-induced aromatase expression appears to occur in an ERK and STAT3 dependent manner since in the presence of either MAPK inhibitor PD 98059 or ERK2 dominant negative as well as in the presence of STAT3 dominant negative the stimulatory effects of leptin on aromatase promoter, enzymatic activity, and aromatase protein content were inhibited (Catalano et al., 2003). Therefore, all of these data taken together suggest that both MAPK and STAT signals converge into stimulating aromatase expression upon leptin exposure. Furthermore, leptin has been shown to upregulate ER expression in breast cancer cells, suggesting that leptin is able to modulate estrogen sensitivity and reinforcing the hypothesis of a direct interaction between the two pathways (Fusco et al, 2010, Yu et al, 2010). In addition to modulation of expression, leptin is also able induce ER nuclear localization together with other typical features of ER functional transactivation in breast cancer cells such as the up-regulation of classic estrogen-dependent genes, in the absence of the natural ligand and through the MAPK pathway (Catalano et al., 2004). A recent study extended the knowledge about estrogen/leptin crosstalk by showing that leptin directs estrogen metabolism toward unfavorable pathways by increasing the formation of DNA adducts. These adducts can then generate mutations resulting in the progression of breast cancer (Shouman et al., 2016). Several lines of evidence suggest that STAT3 may represent the common element responsible for this bidirectional crosstalk between leptin and estrogen signaling and may represent the key factor in leptin-driven hormone-dependent breast cancer (Gao et al, 2007, Binai et al, 2010). As a consequence of this considerable crosstalk, leptin interferes with the action of tamoxifen and ICI 182,780 in estrogen-dependent breast cancer cells and may contribute to antiestrogen resistance (Garofalo et al., 2004, Chen et al, 2013). Taken together, these findings suggest that the leptin system might play a crucial role in breast cancer pathogenesis and progression in the obese and represent a potential novel target for therapeutic intervention in breast cancer (Cirillo et al., 2008). Adiponectin is the most abundant hormone secreted from adipose tissue with physiological plasma concentrations ranging from 3 to 30 μg/ml (Chandran et al., 2003). Adiponectin has been shown to have insulin-sensitizing properties and plays a protective function against obesity-related disorders, including by exhibiting powerful anti-inflammatory properties. In particular, adiponectin inhibits production of inflammatory cytokines, such as TNF-α, in adipose tissue (Maeda et al., 2002). Beyond these metabolic activities, adiponectin may contribute to the development of several cancers, including breast cancer (Panno et al., 2016). In contrast to most adipose-secreted proteins, adiponectin levels are reduced in obesity. These lower serum levels of adiponectin, known as hypoadiponectinemia, have been associated with higher risk of developing postmenopausal breast cancer (Mantzoros et al, 2004, Tworoger et al, 2007). Furthermore, in situ adiponectin receptor 1 (AdipoR1) expression has been reported to be inversely correlated with breast tumor size (Pfeiler et al., 2010). In an in vivo study conducted on transgenic mice, authors have demonstrated that a reduced production of adiponectin was associated with earlier and facilitated mammary tumorigenesis and accelerated tumor growth (Lam et al., 2009). Consistently, adiponectin treatment markedly inhibited tumor growth and distant metastasis of invasive cancer cells in female nude mice (Wang et al., 2006). Dieudonne and colleagues have demonstrated that adiponectin exhibits an anti-proliferative effect on breast cancer and showed that adiponectin inhibited proliferation of MCF-7 breast cancer cells, including by inactivating MAPK signaling cascade, decreasing proliferation-related genes expression such as cyclin D1 and c-myc, and by increasing pro-apoptotic genes expression (Dieudonne et al., 2006). However, other studies have reported conflicting data on the effects elicited by adiponectin on breast cancer cell growth, showing that adiponectin stimulates MCF-7 cell growth or has no noticeable effect on this cell line (Mauro et al., 2014). A relationship between adiponectin and estrogen signaling has been identified in the study conducted by Mauro and colleagues where they demonstrated that ER expression negatively interferes with the anti-proliferative effect induced by adiponectin on breast cancer cell growth, suggesting that adiponectin may exert an anti-proliferative role only in ER-negative breast cancer cells (Mauro et al., 2014). These discrepancies regarding adiponectin effects and ER status are still far from being fully understood and suggest that the cellular response to adiponectin may be dichotomic and dependent on breast cancer phenotype. Despite divergences about the potential anti-proliferative effect of adiponectin, it is now clear that adiponectin also attenuates hormone-dependent breast cancer risk through other molecular mechanisms, including by modulating aromatase transcript expression and estrogen production in adipose stromal cells. While leptin stimulates aromatase expression as described above, adiponectin inhibits the activity of aromatase promoter PII and these effects are at least in part mediated via effects on the LKB1/AMPK/CRTC signaling pathway (Brown et al., 2009). Adiponectin has been found to significantly increase LKB1 expression and activity with a concomitant activation of AMPK and a subsequent down regulation of aromatase expression in human adipose stromal cells. Consistently, adiponectin reduces interaction of CRTC2 and aromatase PII by more than 50% by preventing its translocation into the nucleus (Brown et al., 2009).