Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients
[en] The farnesoid X receptor (FXR, NR1H4), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, is normally produced in the liver and the gastrointestinal tract, where it acts as a bile acid sensor. It has been recently detected in breast cancer cell lines and tissue specimens. The expression of FXR was scored (0-8) by immunohistochemistry on 204 breast cancer samples and correlated with established cancer biomarkers. Moreover, the effect of the FXR activator chenodeoxycholic acid (CDCA) was determined on cell proliferation and estrogen receptor regulation/activation in breast cancer cell lines. FXR was detected in 82.4% of samples with a high median expression score of 5. FXR expression significantly correlated with estrogen receptor (ER) expression (P = 0.009) and luminal-like markers. In ER-positive tumors, FXR expression was significantly correlated with the proliferation marker Ki-67 (P < 0.001) and the nodal status (P = 0.028), but only so in postmenopausal women, suggesting that lack of estrogens may disclose the association between FXR and cell proliferation. In vitro experiments confirmed clinical data since CDCA stimulated the proliferation of ER-positive cells only in steroid-free medium, a stimulation inhibited upon siRNA-silencing of FXR expression as well as ER blockade by antiestrogens. Moreover, co-immunoprecipitation experiments revealed that CDCA activated-FXR interacted with ER. These results suggest that ER-positive breast tumors could be stimulated to proliferate via a crosstalk between FXR and ER, particularly in a state of estrogen deprivation (menopause, aromatase inhibitors).
Disciplines :
Immunology & infectious disease Oncology
Author, co-author :
Journé, Fabrice
Durbecq, Virginie
Chaboteaux, Carole
Rouas, Ghizlane
Laurent, Guy ; Université de Mons > Faculté de Médecine et de Pharmacie > Histologie
Nonclercq, Denis ; Université de Mons > Faculté de Médecine et de Pharmacie > Service d'Histologie
Sotiriou, Christos
Body, Jean-Jacques
Larsimont, Denis
Language :
English
Title :
Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients
Publication date :
01 June 2009
Journal title :
Breast Cancer Research and Treatment
ISSN :
0167-6806
Publisher :
Kluwer Academic Publishers, Netherlands
Volume :
115
Issue :
3
Pages :
523-535
Peer reviewed :
Peer Reviewed verified by ORBi
Research unit :
M118 - Histologie
Research institute :
R550 - Institut des Sciences et Technologies de la Santé
BM Forman E Goode J Chen AE Oro DJ Bradley T Perlmann DJ Noonan LT Burka T McMorris WW Lamph 1995 Identification of a nuclear receptor that is activated by farnesol metabolites Cell 81 687 693
H Wang J Chen K Hollister LC Sowers BM Forman 1999 Endogenous bile acids are ligands for the nuclear receptor FXR/BAR Mol Cell 3 543 553 (Pubitemid 29268438)
M Makishima AY Okamoto JJ Repa H Tu RM Learned A Luk MV Hull KD Lustig DJ Mangelsdorf B Shan 1999 Identification of a nuclear receptor for bile acids Science 284 1362 1365 (Pubitemid 29289663)
DJ Parks SG Blanchard RK Bledsoe G Chandra TG Consler SA Kliewer JB Stimmel TM Willson AM Zavacki DD Moore 1999 Bile acids: natural ligands for an orphan nuclear receptor Science 284 1365 1368 (Pubitemid 29289664)
S Modica A Moschetta 2006 Nuclear bile acid receptor FXR as pharmacological target: are we there yet? FEBS Lett 580 5492 5499 (Pubitemid 44488553)
FY Lee H Lee ML Hubbert PA Edwards Y Zhang 2006 FXR, a multipurpose nuclear receptor Trends Biochem Sci 31 572 580 (Pubitemid 44436939)
PA Edwards HR Kast AM Anisfeld 2002 BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis J Lipid Res 43 2 12 (Pubitemid 34117211)
NY Kalaany DJ Mangelsdorf 2006 LXRS and FXR: the yin and yang of cholesterol and fat metabolism Annu Rev Physiol 68 159 191
T Claudel E Sturm F Kuipers B Staels 2004 The farnesoid X receptor: a novel drug target? Expert Opin Investig Drugs 13 1135 1148 (Pubitemid 39242737)
S Westin RA Heyman R Martin 2005 FXR, a therapeutic target for bile acid and lipid disorders Mini Rev Med Chem 5 719 727 (Pubitemid 41051895)
D Bishop-Bailey DT Walsh TD Warner 2004 Expression and activation of the farnesoid X receptor in the vasculature Proc Natl Acad Sci USA 101 3668 3673 (Pubitemid 38338252)
F He J Li Y Mu R Kuruba Z Ma A Wilson S Alber Y Jiang T Stevens S Watkins 2006 Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells Circ Res 98 192 199 (Pubitemid 43755350)
J Silva S Dasgupta G Wang K Krishnamurthy E Ritter E Bieberich 2006 Lipids isolated from bone induce the migration of human breast cancer cells J Lipid Res 47 724 733
KE Swales M Korbonits R Carpenter DT Walsh TD Warner D Bishop-Bailey 2006 The farnesoid X receptor is expressed in breast cancer and regulates apoptosis and aromatase expression Cancer Res 66 10120 10126 (Pubitemid 44672066)
F Journe G Laurent C Chaboteaux D Nonclercq V Durbecq D Larsimont JJ Body 2008 Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor activation Breast Cancer Res Treat 107 49 61 (Pubitemid 350179595)
V Costarelli TA Sanders 2002 Plasma deoxycholic acid concentration is elevated in postmenopausal women with newly diagnosed breast cancer Eur J Clin Nutr 56 925 927
U Raju M Levitz NB Javitt 1990 Bile acids in human breast cyst fluid: the identification of lithocholic acid J Clin Endocrinol Metab 70 1030 1034
NB Javitt K Budai DG Miller AC Cahan U Raju M Levitz 1994 Breast-gut connection: origin of chenodeoxycholic acid in breast cyst fluid Lancet 343 633 635 (Pubitemid 24087807)
V Costarelli TA Sanders 2002 Plasma bile acids and risk of breast cancer IARC Sci Publ 156 305 306
LM McShane DG Altman W Sauerbrei SE Taube M Gion GM Clark 2006 REporting recommendations for tumor MARKer prognostic studies (REMARK) Breast Cancer Res Treat 100 229 235 (Pubitemid 44631925)
DC Allred JM Harvey M Berardo GM Clark 1998 Prognostic and predictive factors in breast cancer by immunohistochemical analysis Mod Pathol 11 155 168 (Pubitemid 28144151)
M Colozza E Azambuja F Cardoso C Sotiriou D Larsimont MJ Piccart 2005 Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? Ann Oncol 16 1723 1739 (Pubitemid 41631235)
OW Prall B Sarcevic EA Musgrove CK Watts RL Sutherland 1997 Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2 J Biol Chem 272 10882 10894
JS Foster DC Henley A Bukovsky P Seth J Wimalasena 2001 Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function Mol Cell Biol 21 794 810 (Pubitemid 32104728)
CJ Sherr JM Roberts 1995 Inhibitors of mammalian G1 cyclin-dependent kinases Genes Dev 9 1149 1163
A De Gottardi F Touri CA Maurer A Perez O Maurhofer G Ventre CL Bentzen EJ Niesor JF Dufour 2004 The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer Dig Dis Sci 49 982 989 (Pubitemid 39012282)
A De Gottardi JM Dumonceau F Bruttin A Vonlaufen I Morard L Spahr L Rubbia-Brandt JL Frossard WN Dinjens PS Rabinovitch 2006 Expression of the bile acid receptor FXR in Barrett's esophagus and enhancement of apoptosis by guggulsterone in vitro Mol Cancer 5 48
S Shishodia BB Aggarwal 2004 Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis J Biol Chem 279 47148 47158 (Pubitemid 39518371)
S Fredersdorf J Burns AM Milne G Packham L Fallis CE Gillett JA Royds D Peston PA Hall AM Hanby 1997 High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers Proc Natl Acad Sci USA 94 6380 6385
KJ Sweeney A Swarbrick RL Sutherland EA Musgrove 1998 Lack of relationship between CDK activity and G1 cyclin expression in breast cancer cells Oncogene 16 2865 2878 (Pubitemid 28383271)
R Hui AL Cornish RA McClelland JF Robertson RW Blamey EA Musgrove RI Nicholson RL Sutherland 1996 Cyclin D1 and estrogen receptor messenger RNA levels are positively correlated in primary breast cancer Clin Cancer Res 2 923 928 (Pubitemid 26198461)
C Catzavelos N Bhattacharya YC Ung JA Wilson L Roncari C Sandhu P Shaw H Yeger I Morava-Protzner L Kapusta 1997 Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer Nat Med 3 227 230 (Pubitemid 27064710)
CJ Sherr 1996 Cancer cell cycles Science 274 1672 1677
CJ Sherr JM Roberts 1999 CDK inhibitors: positive and negative regulators of G1-phase progression Genes Dev 13 1501 1512 (Pubitemid 29297917)
MK Mateyak AJ Obaya JM Sedivy 1999 c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points Mol Cell Biol 19 4672 4683 (Pubitemid 29289505)
AM Brodie VC Njar 2000 Aromatase inhibitors and their application in breast cancer treatment*Steroids 65 171 179 (Pubitemid 30129250)
MA Blankenstein J van de Ven I Maitimu-Smeele GH Donker PC de Jong J Daroszewski J Szymczak A Milewicz JH Thijssen 1999 Intratumoral levels of estrogens in breast cancer J Steroid Biochem Mol Biol 69 293 297 (Pubitemid 29305549)
FM Nagengast MJ Grubben IP van Munster 1995 Role of bile acids in colorectal carcinogenesis Eur J Cancer 31A 1067 1070
SJ Lewis KW Heaton 1999 The metabolic consequences of slow colonic transit Am J Gastroenterol 94 2010 2016 (Pubitemid 29374525)
AR Carmichael 2006 Obesity as a risk factor for development and poor prognosis of breast cancer BJOG 113 1160 1166 (Pubitemid 44401209)
L Halmy T Feher K Steczek A Farkas 1986 High serum bile acid level in obesity: its decrease during and after total fasting Acta Med Hung 43 55 58
E Cho D Spiegelman DJ Hunter WY Chen MJ Stampfer GA Colditz WC Willett 2003 Premenopausal fat intake and risk of breast cancer J Natl Cancer Inst 95 1079 1085 (Pubitemid 36950112)
V Costarelli TA Sanders 2001 Acute effects of dietary fat composition on postprandial plasma bile acid and cholecystokinin concentrations in healthy premenopausal women Br J Nutr 86 471 477 (Pubitemid 32982195)
LC Harlan RJ Coates G Block RS Greenberg A Ershow M Forman DF Austin V Chen SB Heymsfield 1993 Estrogen receptor status and dietary intakes in breast cancer patients Epidemiology 4 25 31 (Pubitemid 23070113)
LH Kushi JD Potter RM Bostick CR Drinkard TA Sellers SM Gapstur JR Cerhan AR Folsom 1995 Dietary fat and risk of breast cancer according to hormone receptor status Cancer Epidemiol Biomarkers Prev 4 11 19
M Jain AB Miller 1997 Tumor characteristics and survival of breast cancer patients in relation to premorbid diet and body size Breast Cancer Res Treat 42 43 55 (Pubitemid 27056727)
Journe F, Durbecq V, Chaboteaux C, Rouas G, IdBoufker H, Laurent G, Larsimont D, Body J (2008) Farnesoid X receptor in primary breast carcinoma: a new marker to predict bone metastasis? Bone 42(Suppl 1):S97 (abstract 175)