Estrogen receptors (ER), including ER-α and ER-β, are known to regulate multiple
biologic responses in various cell types. The expression of ER-β is lost in various
cancers. ER-β agonists were shown to modulate
inflammation,
cancer cell proliferation, and differentiation. Here, we investigated the
cancer chemopreventive properties of
Erb-041, an ER-β agonist, using a model of UVB-induced photocarcinogenesis in SKH-1 mice.
Erb-041 significantly reduced UVB-induced
carcinogenesis.
Tumor numbers and volume were reduced by 60% and 84%, respectively, in the Erb-041-treated group as compared with UVB (alone) control. This inhibition in
tumorigenesis was accompanied by the decrease in
proliferating cell nuclear antigen (
PCNA),
cyclin D1,
VEGF, and CD31, and an increase in apoptosis. The lost ER-β expression in
squamous cell carcinomas (SCC) was significantly recovered by
Erb-041 treatment. In addition, the UVB-induced inflammatory responses were remarkably reduced.
Myeloperoxidase activity, levels of
cytokines (
interleukin (IL)-1β, IL-6, and IL-10), and expression of p-ERK (
extracellular signal-regulated kinase) 1/2, p-p38, p-IκB, iNOS, COX-2, and nuclear NF-κBp65 were diminished. The number of
tumor-associated inflammatory cells (GR-1(+)/CD11b(+) and F4/80(+)) was also decreased.
Tumors excised from Erb-041-treated animal were less invasive and showed reduced epithelial-mesenchymal transition (EMT). The enhanced expression of
E-cadherin with the concomitantly reduced expression of
N-cadherin, Snail, Slug, and Twist characterized these lesions. The WNT/β-
catenin signaling pathway, which underlies pathogenesis of
skin cancer, was found to be downregulated by
Erb-041 treatment. Similar but not identical changes in proliferation and EMT regulatory
proteins were noticed following treatment of
tumor cells with a WNT signaling inhibitor
XAV939. Our results show that
Erb-041 is a potent
skin cancer chemopreventive agent that acts by dampening the WNT/β-
catenin signaling pathway.