The Role of b-Arrestins in Cancer - Progress in Molecular Biology and Translational Science - page 391

correlatedwith reduced patient survival. In the second cohort, the expression
of ARRB1 was evaluated in 500 premenopausal patients randomized for
receiving Tamoxifen as neo-adjuvant therapy or no-adjuvant therapy. Inter-
estingly, patients with low or moderate levels of stromal ARRB1 protein
expression did not benefit from the neo-adjuvant therapy. 86

3.2. Colorectal cancer
One of the earliest reports investigated the role of ARRB1 in the metastatic
progression of colon cancer. 5 PGE 2 -induced transactivation of the EGF
receptor is mediated by the association of ARRB1 with c-Src. 5 Activation
of this pathway was found to be dependent on ARRB1 and resulted in
increased colon cancer cell proliferation and survival. 5 The activity of
ARRB1 is regulated by phosphorylation at the Ser-412 position, which
controls its association with c-Src. 5,57
Amore recent study examined the role of ARRBs in mice with the trun-
cated tumor suppressor gene, adenomatous polyposis coli (APC). The dis-
ruption of APC induces intestinal tumor growth via an activated Wnt
signaling pathway. Targeted knockdown of ARRB1 did not result in any
significant change in tumor formation, but depletion of ARRB2 levels by
targeted disruption or using RNA interference reduced intestinal tumor ini-
tiation in 67% of the animals. 57 The remaining 33% of animals formed
tumors that were similar in size, characteristics, and gene expression profile
to the control group mice with wild-type ARRB2. In an ex vivo model using
cells isolated from APC D 14/ þ mouse tumors, downregulation of ARRB2
decreased Wnt pathway activity, indicating that the tumor formation in
these mice was dependent on Wnt pathway activity. In spite of the absence
of any other reports evaluating the role of ARRBs in intestinal neoplasms,
these two important studies point to the differential biological role of the
two ARRB proteins and their impact on cancer signaling pathways. While
ARRB1 may play an essential role in the cancer-associated c-Src signaling
pathway, 5 it might not be involved in other pathways such as Wnt signaling,
which have been shown to be dependent on ARRB2. 57

3.3. Lung cancer
Lung cancer is the leading cause of cancer death for men and women in the
United States. 58 There are two major forms of lung cancer; small-cell lung
cancer and NSCLC. Smoking is a significant contributing factor involved in
the initiation and progression of lung cancer. Nicotine, an addictive