The Role of b-Arrestins in Cancer - Progress in Molecular Biology and Translational Science - page 394

the establishment and propagation of chronic myelogenous leukemia
(CML). Using knockout mouse models, loss of ARRB2, but not ARRB1,
led to severe impairment in CML initiation and progression. The effect of
ARRB2 on CML was mediated in part through the Wnt/ b -catenin signal-

ing pathway. 70

3.6. Prostate cancer
Prostate cancer often manifests as an androgen-dependent disease that can be
managed initially through inhibition of the androgen receptor (AR), yet many
patients with seemingly successful treatment will develop reoccurrence of a
more severe androgen-independent, hormone-refractory disease. 71 The
ARRB2 protein in prostate cancer was found to repress AR activity by func-
tioning as a scaffold and forming a complexwith theARandMdm2 resulting in
ubiquitylation and downregulation of the AR. 72 Also, an inverse relationship
betweenPSAprotein expression andARRB2 protein expressionwas observed
in prostate cancer tissue samples. 71 Interestingly, the staining of ARRB2 in the
cancer samples was localized to the epithelial cells and not the stromal cells,
whereas in normal prostate tissue, ARRB2 staining was only observed in the
stromal cells. 71,73 The type III TGF- RIII) expression was found

decreased or lost in the majority of human prostate cancers at the protein and
mRNA level, and restoring expression decreased cell motility, cell invasion,
and tumorigenicity. 74 A follow-up study identified ARRB2 as the essential
scaffolding protein that allowed T

b receptor (T b

b RIII to activate Cdc42 and inhibit cell

migration. 75 Conversely, the 2 AR) is a GPCR asso-

ciatedwith increased activity levels in prostate cancer patients. 76 A recent study
using prostate cancer cells demonstrated that the increased cell proliferation
induced by

b 2 adrenergic receptor ( b

2 AR activation was mediated by an ARRB2 complex with
c-Src. 76 More studies are needed to differentiate the role of ARRB2 in prostate
cancer migration, invasion, and tumorigenicity.

b

3.7. Pancreatic cancer
It has been shown that the chemokine receptors, CXCR4 and CXCR7
are highly overexpressed in pancreatic cancer. 77 Following CXCL12
stimulation, both receptors signal through ARRB2 to activate the MAPK
pathway, which promotes increased cellular proliferation of pancreatic
cells. 77,78 Another signaling pathway dysregulated in pancreatic cancer is
the hedgehog (Hh) pathway. Binding of the ligand sonic hedgehog

(Shh) to Patched (Ptc) relieves the inhibitory control of Ptc over