The antiproliferative role of the liver X receptors in breast and colorectal cancer

The liver X receptors (LXR
α
and LXR
β
) are members of the nuclear receptor superfamily of 
ligand activated transcription factors and have 
functions as regulators of lipid and glucose 
metabolism, as well as inflammatory response. In recent years, several reports have 
demonstrated an important role of LXRs
in the control of cell proliferation. 




In 
Paper I
we demonstrate that LXR activation with synthetic agonist GW3965 leads to a 
strong antiproliferative effect in four different 
human breast cancer cell 
lines. We show that 
LXR activation induces an arrest at the G
1
/S check point of the cell cycle with a 
hypophosphorylation of retinoblasto
ma protein and a downregulation of cell cycle modulators 
such as Skp2, cyclin A2 and cy
clin D1. We further show that 
the antiproliferative function of 
LXRs is independent of lipid biosynthesis. 




In
Paper II
we follow up the results in Paper I to
elucidate more mechanisms of LXR 
activation in human breast cancer cell lines. Us
ing microarray analysis, we find both cell line 
specific and common LXR target 
genes. The common responsive genes that were upregulated 
upon LXR activation are annotated
to known metabolic functions of LXR, while the common 
downregulated genes mostly include those 
with function in cell cycle regulation and 
proliferation. Comparing the common downregulat
ed gene set, with br
east cancer tumour 
samples and patient data we find 
that patients with tumours expr
essing lower levels of these 
LXR target genes had better survival compared 
to patients with a higher expression of these 
genes. In addition, we identify the E2F family 
of transcription factor
s as mediators of the 
antiproliferative effect of LXR activation. 




In 
Paper III
we demonstrate that activa
tion of LXRs with 
GW3965 decreases proliferation in 
human colorectal cell lines with a cell cycle arrest in the G
1
to S phase transition. We 
demonstrate a decreased expression of cell 
cycle promoters such 
as Skp2, CDK1, CDK2, 
CDK4, cyclin E, cyclin B1 and c-myc, as 
well as hypophosphorylation of retinoblastoma 
protein. Moreover, we show that LXR deficient 
mice have an increased proliferation in the 
colonic crypt compared to wild
type mice. Also, activation of
LXRs with GW3965 reduces 
proliferation in the colonic 
crypt of wild type mice. 




In 
Paper IV
we demonstrate that activation of LXRs
dampens the inflammatory response by 
downregulating pro-inflammatory
mediators in two different 
mouse models of colitis. In 
addition, LXR deficient mice have
a faster and more severe di
sease progression. We further 
demonstrate that expression of LXR regulated 
genes is suppressed in colon samples from 
patients with either Crohn’s disease or ulcer
ative colitis compared 
to healthy controls. 
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is 
associated to increased risk of developing colore
ctal cancer. The data in Paper IV suggests the 
potential for LXR mediated inhib
ition of inflammation during IBD,
thus reducing the risk for 
developing colorectal cancer