Breast cancer is the most prevalent
tumor in women worldwide and about 70% patients are
estrogen receptor positive. In these
cancer patients, resistance to the anticancer
estrogen receptor antagonist tamoxifen emerges to be a major clinical obstacle. Peptidyl-
prolyl isomerase Pin1 is prominently overexpressed in
breast cancer and involves in
tamoxifen-resistance. Here, we explore the mechanism and effect of targeting Pin1 using its chemical inhibitor
all-trans retinoic acid (ATRA) in the treatment of
tamoxifen-resistant
breast cancer. We found that Pin1 was up-regulated in
tamoxifen-resistant human
breast cancer cell lines and
tumor tissues from relapsed patients. Pin1 overexpression increased the phosphorylation of ERα on S118 and stabilized ERα
protein. ATRA treatment, resembling the effect of Pin1 knockdown, promoted ERα degradation in
tamoxifen-resistant cells. Moreover, ATRA or Pin1 knockdown decreased the activation of ERK1/2 and AKT pathways. ATRA also reduced the nuclear expression and transcriptional activity of ERα. Importantly, ATRA inhibited cell viability and proliferation of
tamoxifen-resistant human
breast cancer cells in vitro. Slow-releasing ATRA
tablets reduced the growth of
tamoxifen-resistant human
breast cancer xenografts in vivo. In conclusion, ATRA-induced Pin1 ablation inhibits
tamoxifen-resistant
breast cancer growth by suppressing multifactorial mechanisms of
tamoxifen resistance simultaneously, which demonstrates an attractive strategy for treating aggressive and endocrine-resistant
tumors.