Chemokine (C-C Motif) Ligand 2 Mediates the Prometastatic Effect of Dysadherin in Human Breast Cancer Cells

Abstract

Dysadherin, a cancer-associated membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. This study examined the role of dysadherin in breast cancer progression. Expression of dysadherin was found to be highest in breast cancer cell lines and tumors that lacked the estrogen receptor (ER). Knockdown of dysadherin caused increased association of E-cadherin with the actin cytoskeleton in breast cancer cell lines that expressed E-cadherin. However, knockdown of dysadherin could still suppress cell invasiveness in cells that had no functional E-cadherin, suggesting the existence of a novel mechanism of action. Global gene expression analysis identified chemokine (C-C motif) ligand 2 (CCL2) as the transcript most affected by dysadherin knockdown in MDA-MB-231 cells, and dysadherin was shown to regulate CCL2 expression in part through activation of the nuclear factor-KB pathway. The ability of dysadherin to promote tumor cell invasion in vitro was dependent on the establishment of a CCL2 autocrine loop, and CCL2 secreted by dysadherin-positive tumor cells also promoted endothelial cell migration in a paracrine fashion. Finally, experimental suppression of CCL2 in MDA-MB-231 cells reduced their ability to metastasize in vivo . This study shows that dysadherin has prometastatic effects that are independent of E-cadherin expression and that CCL2 could play an important role in mediating the prometastatic effect of dysadherin in ER-negative breast cancer. (Cancer Res 2006; 66(14): 7176-84)

FXYD5 Protein Has a Pro-inflammatory Role in Epithelial Cells

“…Previously, it was reported that knockdown of FXYD5 in MDA-MB-231 breast cancer cells largely decreases expression and secretion of the chemokine CCL2 (12). A related effect has also been observed in renal cell carcinoma cells (7).…”

“…It has been suggested that the increased levels of FXYD5 contributes to a MCP-1 autoregulatory loop downstream of NF-B (12). Moreover, FXYD5 is one of the genes up-regulated in chronic inflammation and immune system overactivity described in the aging process of the human brain (17).…”

In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin

“…The latter possibly acts, either alone or in conjunction with loss of E-cadherin, by allowing cells to dissociate from each other. Studies on the function of dysadherin are available by experimental data, where dysadherin appears to play an important role in neoplastic cell invasion and metastasis (Ino et al, 2002;Nam et al, 2006). The exact molecular mechanisms of these effects have not been elucidated yet.…”

“…Recently, it has been shown that, besides downregulating E-cadherin, dysadherin can promote invasion at least in breast cancer cells in vitro, through an E-cadherinindependent mechanism. This mechanism involves enhanced signaling through the NF-kB pathway, which leads to increased production of the tumour-promoting (C-C motif) ligand 2 (CCL2) (Nam et al, 2006).…”

“…This novel cancer-associated protein has been detected in head and neck, tongue, oesophageal, gastric, colorectal, testicular, pancreatic, thyroid, and cervical carcinomas as well as in malignant melanoma and has been associated with tumour aggressiveness (Ino et al, 2002;Tsuiji et al, 2002;Aoki et al, 2003;Sato et al, 2003;Shimamura et al, 2003Shimamura et al, , 2004Nakanishi et al, 2004;Shimada et al, 2004a, b;Wu et al, 2004;Batistatou et al, 2005;Nishizawa et al, 2005;Batistatou et al, 2006;Kyzas et al, 2006). A recent in vitro study has demonstrated that dysadherin has prometastatic effects that are independent of E-cadherin expression (Nam et al, 2006). The aim of the present study was to investigate further the expression of dysadherin in breast carcinoma, with particular emphasis to the acquisition of a lobular or a ductal phenotype, in combination with E-cadherin expression.…”