Deoxycholate, an Endogenous Tumor Promoter and DNA Damaging Agent, Modulates BRCA-1 Expression in Apoptosis-Sensitive Epithelial Cells: Loss of BRCA-1 Expression in Colonic Adenocarcinomas

Romagnolo, Donato F.; Chirnomas, Ryan B.; Ku, Jennifer; Jeffy, Brandon D.; Payne, Claire M.; Holubec, Hana; Ramsey, Lois; Bernstein, Harris; Bernstein, Carol; Kunke, Kathleen; Bhattacharyya, Achyut K.; Warneke, James; Garewal, Harinder S.

doi:10.1207/s15327914nc4601_11

Cited by 20 publications

(14 citation statements)

References 37 publications

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“…In colon cancer cells, DC has been found to elicit a variety of effects that promote cancer spread and metastasis (21,31,33). We show that in MDA-MB-231 cells, low concentrations of DC induce the uPA cell signaling pathway, whose activation is commonly linked to metastasis formation (24,34,35).…”

Section: Discussionmentioning

confidence: 86%

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

Silva

Dasgupta

Wang

et al. 2006

Journal of Lipid Research

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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...

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Section: Discussionmentioning

confidence: 86%

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

Silva

Dasgupta

Wang

et al. 2006

Journal of Lipid Research

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“…The level and pattern of expression of cytochrome c oxidase subunit I in nonneoplastic colonic crypts was assessed using standard immunohistochemical methods, as previously described (21)(22)(23)(24). Formalin-fixed and paraffin-embedded tissues were cut into 4-Am sections, deparaffinized, and rehydrated.…”

Section: Methodsmentioning

confidence: 99%

Crypt-Restricted Loss and Decreased Protein Expression of Cytochrome c Oxidase Subunit I as Potential Hypothesis-Driven Biomarkers of Colon Cancer Risk

Payne¹,

Holubec²,

Bernstein³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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There is an increasing demand for the development of intermediate biomarkers to assess colon cancer risk. We previously determined that a live cell bioassay, which assesses apoptosis resistance in the nonneoplastic colonic mucosa, detects f50% of patients with colon cancer. A hypothesis-driven biomarker that reflects apoptosis resistance in routine formalin-fixed, paraffin-embedded tissue would be easier to use. Cytochrome c oxidase is a critical enzyme that controls mitochondrial respiration and is central to apoptosis. We did an immunohistochemical study of cytochrome c oxidase subunit I expression in 46 colonic mucosal samples from 16 patients who had undergone a colonic resection. These included five patients without evidence of colonic neoplasia (three normal and two diverticulitis), three patients with tubulovillous adenomas, and eight patients with colonic adenocarcinomas. Analysis of aberrancies in expression of cytochrome c oxidase subunit I showed that, compared with nonneoplasia, the patients with neoplasia had a higher mean incidence of crypts having decreased expression (1.7 versus 22.8, P = 0.03) and a higher mean incidence having crypt-restricted loss (0.6 versus 3.2, P = 0.06). The percentage with segmented loss was low and was similar in the two groups. Combining these results, the mean % normal (i.e., with none of the three types of abnormality) was 96.7 in nonneoplasia versus only 73.2 in patients with neoplasia (P = 0.02).

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“…Thus, DCA has genotoxic effects, which are believed to be secondary to induction of oxidative stress in the cell [74] , and suppresses the p53 response to DNA damage, an action that is at least partly dependent on ERK signaling [75] . Moreover, inhibition of BRCA-1 by relatively high DCA concentrations contributes to defective DNA repair [76] . Recently DCA and LCA (in conjugated form) were shown to elicit transactivation of the epidermal growth factor receptor via interaction with muscarinic receptors and phosphorylation of ERK [77] .…”

Section: Ba and Colorectal Cancermentioning

confidence: 99%

Intestinal bile acid physiology and pathophysiology

Martínez‐Augustin¹,

Medina²

2008

WJG

135

114

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Bile acids (BAs) have a long established role in fat digestion in the intestine by acting as tensioactives, due to their amphipathic characteristics. BAs are reabsorbed very efficiently by the intestinal epithelium and recycled back to the liver via transport mechanisms that have been largely elucidated. The transport and synthesis of BAs are tightly regulated in part by specific plasma membrane receptors and nuclear receptors. In addition to their primary effect, BAs have been claimed to play a role in gastrointestinal cancer, intestinal inflammation and intestinal ionic transport. BAs are not equivalent in any of these biological activities, and structural requirements have been generally identified. In particular, some BAs may be useful for cancer chemoprevention and perhaps in inflammatory bowel disease, although further research is necessary in this field. This review covers the most recent developments in these aspects of BA intestinal biology.

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Deoxycholate, an Endogenous Tumor Promoter and DNA Damaging Agent, Modulates BRCA-1 Expression in Apoptosis-Sensitive Epithelial Cells: Loss of BRCA-1 Expression in Colonic Adenocarcinomas

Cited by 20 publications

References 37 publications

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

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

Crypt-Restricted Loss and Decreased Protein Expression of Cytochrome c Oxidase Subunit I as Potential Hypothesis-Driven Biomarkers of Colon Cancer Risk

Intestinal bile acid physiology and pathophysiology

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