Estrogen Receptor-α36 Is Involved in Pterostilbene-Induced Apoptosis and Anti-Proliferation in In Vitro and In Vivo Breast Cancer

Abstract

Pterostilbene (trans-3,5-dimethoxy-4′-hudroxystilbene) is an antioxidant primarily found in blueberries. It also inhibits breast cancer regardless of conventional estrogen receptor (ER-α66) status by inducing both caspase-dependent and caspase-independent apoptosis. However, the pterostilbene-induced apoptosis rate in ER-α66-negative breast cancer cells is much higher than that in ER-α66-positive breast cancer cells. ER-α36, a variant of ER-α66, is widely expressed in ER-α66-negative breast cancer, and its high expression mediates the resistance of ER-α66-positive breast cancer patients to tamoxifen therapy. The aim of the present study is to determine the relationship between the antiproliferation activity of pterostilbene and ER-α36 expression in breast cancer cells. Methyl-thiazolyl-tetrazolium (MTT) assay, apoptosis analysis, and an orthotropic xenograft mouse model were used to examine the effects of pterostilbene on breast cancer cells. The expressions of ER-α36 and caspase 3, the activation of ERK and Akt were also studied through RT-PCR, western blot analysis, and immunohistochemical (IHC) staining. ER-α36 knockdown was found to desensitize ER-α66-negative breast cancer cells to pterostilbene treatment both in vitro and in vivo, and high ER-α36 expression promotes pterostilbene-induced apoptosis in breast cancer cells. Western blot analysis data indicate that MAPK/ERK and PI3K/Akt signaling in breast cancer cells with high ER-α36 expression are mediated by ER-α36, and are inhibited by pterostilbene. These results suggest that ER-α36 is a therapeutic target in ER-α36-positive breast cancer, and pterostilbene is an inhibitor that targets ER-α36 in the personalized therapy against ER-α36-positive breast cancer.

Differential Anticancer Activity of Pterostilbene Against Three Subtypes of Human Breast Cancer Cells

“…Therefore, these data suggest that pterostilbene may execute its apoptotic effect primarily through blocking AKT/mTORmediated signaling pathways in triple-negative cells. Similar pterostilbene-induced apoptosis through suppression of AKT signaling pathway has been reported in breast cancer and colon cancer cell lines (16,27). Furthermore, pterostilbene also induces apoptosis in human oral cancer cell lines by reducing phosphorylation of AKT and mTOR (28).…”

“…Moreover, it is more potent than resveratrol in inhibiting the growth of human colon cancer cells as well as preventing azoxymethaneinduced colonic tumorigenesis (14). Although the excellent antioxidant property of pterostilbene is most likely the basis for its preventive role against cancer at the initiating and progression stages, increasing evidence indicates that pterostilbene has anticancer activity against a variety types of human cancer cells through modulation of diverse molecular targets involving growth factor signaling, cell-cycle regulation, and cell survival/apoptosis (15)(16)(17). In animal studies, pterostilbene inhibited the growth of pancreatic and breast cancer in xenotransplanted nude mice (16,18).…”

Pterostilbene inhibits hepatocellular carcinoma through p53/SOD2/ROS-mediated mitochondrial apoptosis

“…Hsiao et al showed that PTE stimulated mitochondrial-derived apoptosis in human acute myeloid leukemia cell lines (30). Pan et al showed that PTE exhibited a pro-apoptotic and anti-proliferation effect in breast cancer (31). In the present study, we also examined the effect of PTE on apoptosis in vivo and in vitro.…”

Pterostilbene down‐regulates hTERT at physiological concentrations in breast cancer cells: Potentially through the inhibition of cMyc

“…Pterostilbene has also been shown to exhibit antioxidative, antiproliferative, and anticancerous properties . A recent study revealed that treatment of MCF‐7 and Bcap‐37 breast cancer cells with pterostilbene induced apoptosis, G1 cell cycle arrest, and cyto‐protective autophagy .…”