title: 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.
authors.affiliation: Cancer Institute, Second Affiliated Hospital, Medicine School of Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Surgical Oncology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yiwang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Surgical Oncology, Second Affiliated Hospital, Medicine School of Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medical Microbiology & Immunology, Medical School of Creighton University, Omaha, Nebraska, United States of America.
authors.forename: Zhaoyi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Second Affiliated Hospital, Medicine School of Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jianjin
authors.initials: J
authors.lastname: Huang
authors.affiliation: Cancer Institute, Second Affiliated Hospital, Medicine School of Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Suzhan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Second Affiliated Hospital, Medicine School of Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ding
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047628:Estrogen Receptor alpha; D013267:Stilbenes; C107773:pterostilbene; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt