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SHARPIN stabilizes estrogen receptor ? and promotes breast cancer cell proliferation.

ABSTRACT: Estrogen receptor ? is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. In our study, we identified the novel E3 ubiquitin ligase SHARPIN function to facilitate ER? signaling. SHARPIN is highly expressed in human breast cancer and correlates with ER? protein level by immunohistochemistry. SHARPIN expression level correlates with poor prognosis in ER? positive breast cancer patients. SHARPIN depletion based RNA-sequence data shows that ER? signaling is a potential SHARPIN target. SHARPIN depletion significantly decreases ER? protein level, ER? target genes expression and estrogen response element activity in breast cancer cells, while SHARPIN overexpression could reverse these effects. SHARPIN depletion significantly decreases estrogen stimulated cell proliferation in breast cancer cells, which effect could be further rescued by ER? overexpression. Further mechanistic study reveals that SHARPIN mainly localizes in the cytosol and interacts with ER? both in the cytosol and the nuclear. SHARPIN regulates ER? signaling through protein stability, not through gene expression. SHARPIN stabilizes ER? protein via prohibiting ER? protein poly-ubiquitination. Further study shows that SHARPIN could facilitate the mono-ubiquitinaiton of ER? at K302/303 sites and facilitate ERE luciferase activity. Together, our findings propose a novel ER? modulation mechanism in supporting breast cancer cell growth, in which SHARPIN could be one suitable target for development of novel therapy for ER? positive breast cancer.

SUBMITTER: Zhuang T

PROVIDER: S-EPMC5652769 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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SHARPIN stabilizes estrogen receptor α and promotes breast cancer cell proliferation.

Zhuang Ting T Yu Sifan S Zhang Lichen L Yang Huijie H Li Xin X Hou Yingxiang Y Liu Zhenhua Z Shi Yuanyuan Y Wang Weilong W Yu Na N Li Anqi A Li Xuefeng X Li Xiumin X Niu Gang G Xu Juntao J Hasni Muhammad Sharif MS Mu Kun K Wang Hui H Zhu Jian J

Oncotarget 20170819 44

Estrogen receptor α is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. In our study, we identified the novel E3 ubiquitin ligase SHARPIN function to facilitate ERα signaling. SHARPIN is highly expressed in human breast cancer and correlates with ERα protein level by immunohistochemistry. SHARPIN expression level correlates with poor prognosis in ERα positive breast cancer patients. SHARPIN depletion based RNA-sequence data shows that ERα signaling ...[more]

PMID: 29100376

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Project description:Breast cancer resistance to the antiestrogens tamoxifen (OHT) and fulvestrant is accompanied by alterations in both estrogen-dependent and estrogen-independent signaling pathways. Consequently, effective inhibition of both pathways may be necessary to block proliferation of antiestrogen-resistant breast cancer cells. In this study, we examined the effects of apigenin, a dietary plant flavonoid with potential anticancer properties, on estrogen-responsive, antiestrogen-sensitive MCF7 breast cancer cells and two MCF7 sublines with acquired resistance to either OHT or fulvestrant. We found that apigenin can function as both an estrogen and an antiestrogen in a dose-dependent manner. At low concentrations (1 mumol/L), apigenin stimulated MCF7 cell growth but had no effect on the antiestrogen-resistant MCF7 sublines. In contrast, at high concentrations (>10 mumol/L), the drug inhibited growth of MCF7 cells and the antiestrogen-resistant sublines, and the combination of apigenin with either OHT or fulvestrant showed synergistic, growth-inhibitory effects on both antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. To further elucidate the molecular mechanism of apigenin as either an estrogen or an antiestrogen, effects of the drug on estrogen receptor-alpha (ERalpha); transactivation activity, mobility, stability, and ERalpha-coactivator interactions were investigated. Low-dose apigenin enhanced receptor transcriptional activity by promoting interaction between ERalpha and its coactivator amplified in breast cancer-1. However, higher doses (>10 mumol/L) of apigenin inhibited ERalpha mobility (as determined by fluorescence recovery after photobleaching assays), down-regulated ERalpha and amplified in breast cancer-1 expression levels, and inhibited multiple protein kinases, including p38, protein kinase A, mitogen-activated protein kinase, and AKT. Collectively, these results show that apigenin can function as both an antiestrogen and a protein kinase inhibitor with activity against breast cancer cells with acquired resistance to OHT or fulvestrant. We conclude that apigenin, through its ability to target both ERalpha-dependent and ERalpha-independent pathways, holds promise as a new therapeutic agent against antiestrogen-resistant breast cancer.

Dataset Information

SHARPIN stabilizes estrogen receptor ? and promotes breast cancer cell proliferation.

Publications

SHARPIN stabilizes estrogen receptor α and promotes breast cancer cell proliferation.

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