Biology Reference
In-Depth Information
to the metastatic potential of breast cancer cells.
52
PAR-2 expression is
linked to cancer cell migration by G protein-independent pathways through
ARRB scaffolding. When activated by trypsin, PAR-2 increases breast
cancer cell migration through ERK1/2 activation. This process has been
found to be dependent on ARRBs.
44
Knockdown of ARRBs by RNA
interference, or the use of a MEK-1 inhibitor, decreased breast cancer cell
migration.
44
These data demonstrate a requirement for both ARRBs in
PAR-2-mediated motility and suggest that autocrine activation of PAR-2
by secreted proteases may contribute to the migration of metastatic tumor
cells through ARRB-dependent ERK1/2 activation.
44
The significance
of this study was that it was one of the earliest reports to indicate the novel
functions of ARRBs other than their well-characterized role as G-protein
signal terminators.
More recent studies further support the role of ARRBs in breast cancer.
ARRBs have been shown to be involved in LPA receptor signaling. LPA is a
biologically active phospholipid that can regulate several cellular processes by
the activation of specific GPCRs. LPA plays a key role in
de novo
lipid synthesis
and also regulates cellular phenotypes such as cell migration, cytoskeletal reor-
ganization, and survival. The role of LPA in breast cancer cell migration, inva-
sion, and metastases is well documented,
53-56
and evidence suggests that
ARRBs mediate the effects of LPA on cancer cells migration through a
Ral GTPase-dependent pathway.
42
The majority of the studies that have explored the role of the ARRBs in
cancer were performed in cell models. Fewer studies have been designed to
explore the clinical relevance of ARRBs expression in disease outcomes such
as response to chemotherapeutic agents. Using a real-time PCR-based assay, Li
et al.
42
detected high levels of both ARRBs in advanced stage breast cancer
tissues compared to early stage disease. In the same study, they examined the
mRNA expression of the two molecules in a breast cancer cell line MDA
MB-231 and thenormalmammary epithelial lineMCF10A.While theprotein
levels of bothARRBswere increased compared to theMCF10Acells, only the
mRNA of the ARRB1 was elevated. The mechanism by which the ARRB2
protein increases but the mRNA does not increase is yet to be characterized.
A single recent study investigated the clinical relevance of ARRB1
expression in tumor and stromal cells and correlated the levels of tissue expres-
siondetectedby immunohistochemical analysiswithdisease outcomes such as
histological grade, tumor size, and node status in two large cohorts of breast
cancer patients. In the first cohort of 179 pre- and postmenopausal patients,
higher expression of ARRB1 in the stroma, but not the tumor cells,
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