Lipids isolated from bone induce the migration of human breast cancer cells

Abstract

Bone is the most common site to which breast cancer cells metastasize. We found that osteoblast-like MG63 cells and human bone tissue contain the bile acid salt sodium deoxycholate (DC). MG63 cells take up and accumulate DC from the medium, suggesting that the bone-derived DC originates from serum. DC released from MG63 cells or bone tissue promotes cell survival and induces the migration of metastatic human breast cancer MDA-MB-231 cells. The bile acid receptor farnesoid X receptor (FXR) antagonist Z-guggulsterone prevents the migration of these cells and induces apoptosis. DC increases the gene expression of FXR and induces its translocation to the nucleus of MDA-MB-231 cells. Nuclear translocation of FXR is concurrent with the increase of urokinase-type plasminogen activator (uPA) and the formation of F-actin, two factors critical for the migration of breast cancer cells. Our results suggest a novel mechanism by which DC-induced increase of uPA and binding to the uPA receptor of the same breast cancer cell selfpropel its migration and metastasis to the bone.-Silva, J., S. Dasgupta, G. Wang, K. Krishnamurthy, E. Ritter, and E. Bieberich. Lipids isolated from bone induce the migration of human breast cancer cells. The migration of cancer cells is a key factor in metastasis, which is a multistep event that involves the interaction of host and tumor tissue. Bone is the most common site to which breast cancer cells metastasize (1, 2). The mechanism underlying this specific metastatic behavior is not completely understood. Recently, we reported that oxygenated derivatives of cholesterol (oxysterols) synthesized and released by human osteoblast-like MG63 cells induce the migration of nonmetastatic human breast cancer MCF-7 cells (3). Bile acids, another species of oxygenated cholesterol, have long been implicated in the tumorigenesis of colorectal cancer (4, 5). Recent studies have shown that an increased concentration of bile acids in breast cyst fluid is indicative of a higher risk of developing breast cancer (6, 7). It remained to be elucidated, however, which cell signaling pathways for tumorigenesis and breast cancer cell migration are triggered by bile acids.The secondary bile acid deoxycholic acid or its salt deoxycholate (DC) is synthesized by intestinal bacteria and transported to the liver and other tissues by the serum (8-11). The specific enrichment of deoxycholic acid and other bile acids in breast cyst fluid shows that tissues other than liver can take up and accumulate bile acids from the serum (7,12,13). Bile acids bind to the nuclear receptor farnesoid X receptor (FXR) and activate a variety of genes involved in cholesterol metabolism and transport (14-17). FXR is expressed in colorectal tumor cells; however, it is not clear how bile acid-induced activation of FXR triggers cancerogenesis (18). In this study, we show for the first time that bone tissue and MG63 cells contain DC. We provide evidence that DC is taken up from the medium and can be released at a concentration that induces the mi...

Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients

“…The nuclear receptor FXR has been recently demonstrated in breast cancer as well as in normal mammary tissue [13][14][15]. The present study reveals a higher FXR expression in ER-positive luminal-like tumors, as compared to ER-negative breast tumors.…”

“…Surprisingly, we and others have also found FXR expression in breast cancer tissue and breast cancer cell lines [13][14][15]. With regard to breast cancer development, the presence of high plasma levels of deoxycholic acid in postmenopausal breast cancer patients, as compared to healthy controls matched for age and body mass index, has been documented, suggesting that this bile acid might be involved in mammary gland carcinogenesis [16].…”

“…Finally, a recent study indicates that the bile acid salt sodium deoxycholate (DC) may promote the survival and the migration of the metastatic MDA-MB-231 cell line through the induction of urokinase-type plasminogen activator, a critical factor for the dissemination of breast cancer cells [13]. These data suggest that, in addition to the involvement of FXR in cell survival/proliferation, this nuclear receptor could be involved in tumor invasiveness/ metastasis, as further supported by the significant correlation between FXR expression and nodal status in our population.…”

Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

“…Data from this assay was consistent with the transwell assay; while significant migration could be observed over the 24 hour incubation period, there was no significant increase when MCF-7 or MDA-MB-231 cells were exposed to FXR agonists (Figure 7b). This data appears in conflict with that of Silva et al, who demonstrated that the secondary bile acid deoxycholate could induce migration of MDA-MB-231, but not MCF-7 cells [48].…”

Hyphenated Tools for Phospholipidomics

“…Structural diversity of each lipid or lipid class will have a distinct effect on membrane properties (i.e., fluidity, permeability, oxygen scavenging, etc.). [4][5][6][7][8][9][10][11][12][13][14][15] Therefore, the potential advantage of the combined use of HPLC, MS, and NMR spectroscopy should be explored. Many studies have explored the analysis of lipids, but to our knowledge a combinatorial approach has rarely been used.…”