Carcinogenesis Advance Access originally published online on January 23, 2009
Carcinogenesis 2009 30(4):575-579; doi:10.1093/carcin/bgp029
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The oxysterol receptor LXR inhibits proliferation of human breast cancer cells
1 Department of Biosciences and Nutrition at NOVUM, Karolinska Institutet, S-141 57 Huddinge, Sweden
2 Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, S-141 86 Huddinge, Sweden
* To whom correspondence should be addressed. Tel: +46 8 608 3339; Fax: +46 8 774 5538; Email: knut.steffensen{at}ki.se
The oxysterol receptors [liver X receptors (LXR
and LXRβ)] regulate cholesterol and lipid biosynthesis and several studies link dysregulation of these metabolic pathways to aberrant cell growth. Here, we show that activation of LXR significantly reduced proliferation in several human breast cancer cells lines. LXR suppressed messenger RNA and/or protein expression of Skp2, cyclin A2, cyclin D1 and estrogen receptor (ER) , whereas it increased the expression of p53 at the protein level and maintained the retinoblastoma protein in a hypophosphorylated active form. These changes may constitute part of the molecular mechanisms behind the antiproliferative effect of LXR. Furthermore, activation of LXR induced expression of key lipogenic genes including sterol regulatory element-binding protein 1c (SREBP1c), fatty acid synthase and stearoyl-coenzyme A desaturase 1, leading to increased triglyceride production in MCF7 cells. Small interfering RNA knockdown of SREBP1c, a master regulator of the lipid biosynthesis, did not abolish the antiproliferative effect of LXR in these cells. Combined these studies identify LXRs as both antiproliferative and lipogenic factors in breast cancer cells and indicate that the antiproliferative effect of LXRs is independent of lipid biosynthesis.
Abbreviations: BrdU, bromodeoxyuridine; DMSO, dimethyl sulfoxide; E2, estradiol; ER, estrogen receptor; FAS, fatty acid synthase; FBS, fetal bovine serum; LXR, liver X receptor; mRNA, messenger RNA; Rb, retinoblastoma; SCD1, stearoyl-coenzyme A desaturase 1; siRNA, small interfering RNA; SREBP1c, sterol regulatory element-binding protein 1c; TG, triglyceride
Received July 14, 2008; revised January 15, 2009; accepted January 18, 2009.
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