Journal
PLOS ONE
Volume 9, Issue 8, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0104459
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Funding
- LD's Zhejiang qianjiang talents project [2011R10029]
- Zhejiang medicine scientific research fund projects [2010ZB073]
- SZZ's National Natural Science Foundation of China [81102012, 91229104]
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Pterostilbene (trans-3,5-dimethoxy-49-hudroxystilbene) is an antioxidant primarily found in blueberries. It also inhibits breast cancer regardless of conventional estrogen receptor (ER-alpha 66) status by inducing both caspase-dependent and caspase-independent apoptosis. However, the pterostilbene-induced apoptosis rate in ER-alpha 66-negative breast cancer cells is much higher than that in ER-alpha 66-positive breast cancer cells. ER-alpha 36, a variant of ER-alpha 66, is widely expressed in ER-alpha 66-negative breast cancer, and its high expression mediates the resistance of ER-alpha 66-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-alpha 36 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-alpha 36 and caspase 3, the activation of ERK and Akt were also studied through RT-PCR, western blot analysis, and immunohistochemical (IHC) staining. ER-alpha 36 knockdown was found to desensitize ER-alpha 66-negative breast cancer cells to pterostilbene treatment both in vitro and in vivo, and high ER-alpha 36 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-alpha 36 expression are mediated by ER-alpha 36, and are inhibited by pterostilbene. These results suggest that ER-alpha 36 is a therapeutic target in ER-alpha 36-positive breast cancer, and pterostilbene is an inhibitor that targets ER-alpha 36 in the personalized therapy against ER-alpha 36-positive breast cancer.
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