Alcohol promotes breast cancer cell invasion by regulating the Nm23-ITGA5 pathway

Abstract

BackgroundAlcohol consumption is an established risk factor for breast cancer metastasis. Yet, the mechanism by which alcohol promotes breast cancer metastases is unknown. The ability of cancer cells to invade through tissue barriers (such as basement membrane and interstitial stroma) is an essential step towards establishing cancer metastasis. In the present study, we identify and examine the roles of two genes, Nm23 and ITGA5, in alcohol-induced breast cancer cell invasion.MethodsHuman breast cancer T47D cells were treated with ethanol at various concentrations. Boyden chamber invasion assays were used to measure cellular invasive ability. The mRNA expression level of metastasis suppressor genes including Nm23 was determined by qRT-PCR. ITGA5 was identified using a qRT-PCR array of 84 genes important for cell-cell and cell-extracellular matrix interactions. Nm23 overexpression in addition to Nm23- and ITGA5 knock-down were used to determine the role of the Nm23-ITGA5 pathway on cellular invasive ability of T47D cells. Protein expression levels were verified by Western blot.ResultsAlcohol increased the invasive ability of human breast cancer T47D cells in a dose-dependent manner through the suppression of the Nm23 metastatic suppressor gene. In turn, Nm23 down-regulation increased expression of fibronectin receptor subunit ITGA5, which subsequently led to increased cellular invasion. Moreover, Nm23 overexpression was effective in suppressing the effects of alcohol on cell invasion. In addition, we show that the effects of alcohol on invasion were also inhibited by knock-down of ITGA5.ConclusionsOur results suggest that the Nm23-ITGA5 pathway plays a critical role in alcohol-induced breast cancer cell invasion. Thus, regulation of this pathway may potentially be used to prevent the establishment of alcohol-promoted metastases in human breast cancers.

Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

“…Alcohol-induced mobility may result from the interaction with the extracellular matrix (EMC) and reorganization of the cytoskeleton system [38, 39]. Alcohol also increases the invasive potential of breast cancer cells [37, 40–42]. The increased invasion is likely mediated by the enhanced ability of breast cancer cells to degrade the EMC, in which matrix metalloproteinases (MMPs) play an important role [40, 41].…”

Links between Alcohol Consumption and Breast Cancer: A Look at the Evidence

“…Ethanol activates MMP-2 production by fibroblasts in a dose-dependent manner and culture medium collected from ethanol-exposed fibroblasts significantly alters the invasive behavior of breast cancer cells and mammary epithelial cells [128]. In addition, a recent in vitro study showed that ethanol promotes the adhesion of breast cancer cells to fibronectin, an important component of the extracellular matrix through suppression of the Nm23 meta-static suppressor gene and subsequent enhancement of fibronectin receptor ITGA5 expression [129]. Ethanol stimulates migration and invasion of breast cancer cells [129], particularly those overexpressing HER2 [130].…”

Integrin α5β1, the Fibronectin Receptor, as a Pertinent Therapeutic Target in Solid Tumors

“…In a subset of breast cancers, overexpression of Steroid Receptor Coactivator-1 (SRC-1) was associated with an upregulation of α5β1 integrin and promotion of α5β1 integrin-dependent cell adhesion and migration [84]. Inverse relationship between α5β1 integrin expression and tumor suppressors expression such as nischarin [85], metastasis suppressors such as Nm23 [86] or epithelial cell-cell adhesion marker such as E-cadherin [87] were reported and associated with impact on breast cell tumorigenic potential. Loss of E-cadherin was also achieved through stimulation of breast cancer cells by angiopoietin-2 which stimulated cell migration through an α5β1 integrin-dependent way [88].…”