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.
Highlights
Breast cancer is the most common malignant tumor in women, and its incidence in the world is persistently rising [1]
MCF-7/ER36 overexpressed ER-a36 compared to MCF-7 cells. b-actin gene expression was used as the internal control (Fig. 1A)
The p-ERK1/2 and p-Akt expressions in Mb231/Si36 were nearly undetected with or without pterostilbene treatment. These results indicate that ERa36 mediates pterostilbene to inhibit MAPK/ERK and Phosphatidylinositol 3-kinase (PI3K)/Akt phosphorylation in breast cancer cells, and ER-a36 knockdown totally deactivates ERK1/2 and Akt phosphorylation in Mb231/ Si36 cells
Summary
Breast cancer is the most common malignant tumor in women, and its incidence in the world is persistently rising [1]. It is a hormone-related systemic disease, and endocrine therapy effectively blocks its estrogen receptor (ER-a66, the classic estrogen receptor) pathway to inhibit tumor progression. ER-a66 expression is an important indicator of breast cancer, and previous studies show that patients with ER-a66-negative tumors have shorter disease-free intervals and worse overall survival than patients with ER-a66-positive tumors [2,3]. Tamoxifen (TAM, the selective estrogen receptor modulator) is the most effective drug commonly used for the endocrine therapy of ER-a66-positive breast cancer patients [4]. Finding new therapeutic strategies is an urgent topic in breast cancer research nowadays
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