As breast cancer cells are able to produce estrogen in vitro, the binding of estrogen to the estrogen receptor α (ERα) may activate downstream PI3K/Akt and MAPK/ERK pathways to promote
cell migration [29, 30]. In a recent study, it was reported that estrogen negatively regulates Nm23 expression in vitro [31]. Thus, the modulation of Nm23 expression shown in this study as a result of alcohol exposure may be mediated by estrogen levels. As a NDP kinase, Nm23 may modify cytoskeleton organization and protein trafficking, possibility through ITGA5, to promote cell migration and adhesion to the extracellular matrix (ECM). Previous studies have shown that Nm23 decreases activity of Rac1, a specific nucleotide exchange factor, through click here binding of Tiam1 [32, 33]. Reduction of Rac1 activation induces the activity of RhoA, a component in the ITGA5-mediated cellular adhesion and migration signalling pathway [34, 33]. Indeed, estrogen has been
PF-573228 nmr found to activate RhoA and this activity is necessary for cytoskeletal remodelling and for the enhancement of breast cancer cell migration and invasion [35]. Thus, down-regulation of Nm23 by alcohol may promote RhoA activation through estrogen regulation to favor ITGA5-mediated breast cancer progression. The ECM and adhesion molecules play a critical role in the invasive phenotype of cancer cells [36]. For example, the binding of integrins to ECM proteins stimulates the phosphorylation of focal adhesion kinase (FAK); this activated FAK can activate signaling pathways such as PI3K, MAPK, and ERK [37]. These pathways have been shown to regulate cell adhesion, motility, invasion, and metastasis [38]. Integrins are heterodimer cell surface receptors composed of α and β subunits. The integrin α5 subunit (ITGA5) dimerizes exclusively with the β1 integrin (ITGB1) Thiamet G to form the classic fibronectin receptor (α5/β1 or ITGA5B1) [39]. The interaction of α5/β1 with fibronectin (FN) plays an important role in the adhesion of cancer
cells to the extracellular matrix [40]. Moreover, previous studies have shown that interaction of α5/β1 with FN promotes activation of the ERK and PI3K signaling pathways, which in turn stimulates cells to invade and produce MMPs (e.g., MMP-1 MMP-9) to facilitate invasion [41]. In our studies, we show that the integrin α5 subunit expression is necessary for alcohol to increase the invasive ability of T47D breast cancer cells. It is possible that alcohol stimulates signaling pathways such as ERK and PI3K, via α5/β1, which then increases the invasive phenotype of T47D breast cancer cells. Consequently, activated integrins may facilitate the movement and metastasis of breast cancer cells. In future studies, we will determine if alcohol affects signaling pathways such as FAK, ERK, and PI3K via ITGA5 and elucidate the role of estrogen in alcohol-mediated down-regulation of Nm23.
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