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Carcinogenesis Advance Access published online on January 23, 2009
Carcinogenesis, doi:10.1093/carcin/bgp029
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The oxysterol receptor LXR inhibits proliferation of human breast cancer cells

Lise-Lotte Vedin1, Sebastian Aleksander Lewandowski1, Paolo Parini1,2, Jan-Åke Gustafsson1 and Knut R. Steffensen1,*

1 Department of Biosciences and Nutrition at NOVUM, Karolinska Institutet, Huddinge, Sweden
2 Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Sweden

* Address correspondence to: Knut R. Steffensen, Department of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, SWEDEN, E-mail: knut.steffensen{at}ki.se, Phone: +46 8 608 3339 ; Fax: +46 8 774 5538

The nuclear receptors LXR{alpha} 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 mRNA and/or protein expression of Skp2, cyclin A2, cyclin D1 and ER{alpha} while it increased expression of p53 at the protein level and maintained the Rb protein in a hypophosphorylated active form. These changes may constitute part of the molecular mechanisms behind the anti-proliferative effect of LXR. Furthermore, activation of LXR induced expression of key lipogenic genes including SREBP1c, FAS and SCD1, leading to increased triglyceride production in MCF7 cells. siRNA knock down of SREBP1c, a master regulator of the lipid biosynthesis, did not abolish the anti-proliferative effect of LXR in these cells. Combined these studies identify LXRs as both anti-proliferative and lipogenic factors in breast cancer cells and indicate that the anti-proliferative effect of LXRs is independent of lipid biosynthesis.

Received July 14, 2008; revised January 15, 2009; accepted January 18, 2009.


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