The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
20531310
DOI
10.1038/onc.2010.228
PII: onc2010228
Knihovny.cz E-resources
- MeSH
- Antineoplastic Agents, Hormonal pharmacology MeSH
- Humans MeSH
- Mucoproteins MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms drug therapy genetics metabolism pathology MeSH
- Oncogene Proteins MeSH
- Prognosis MeSH
- Proteins metabolism MeSH
- Tamoxifen pharmacology MeSH
- Transfection MeSH
- Cell Survival drug effects physiology MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- AGR2 protein, human MeSH Browser
- Antineoplastic Agents, Hormonal MeSH
- Mucoproteins MeSH
- Oncogene Proteins MeSH
- Proteins MeSH
- Tamoxifen MeSH
Transcriptomic screens in breast cancer cell lines have identified a protein named anterior gradient-2 (AGR2) as a potentially novel oncogene overexpressed in estrogen receptor (ER) positive tumours. As targeting the ER is responsible for major improvements in cure rates and prevention of breast cancers, we have evaluated the pro-oncogenic function of AGR2 in anti-hormone therapeutic responses. We show that AGR2 expression promotes cancer cell survival in clonogenic assays and increases cell proliferation and viability in a range of cancer cell lines. Chromatin immunoprecipitation and reporter assays indicate that AGR2 is transcriptionally activated by estrogen through ERalpha. However, we also found that AGR2 expression is elevated rather than inhibited in response to tamoxifen, thus identifying a novel mechanism to account for an agonistic effect of the drug on a specific pro-oncogenic pathway. Consistent with these data, clinical analysis indicates that AGR2 expression is related to treatment failure in ERalpha-positive breast cancers treated with tamoxifen. In contrast, AGR2 is one of the most highly suppressed genes in cancers of responding patients treated with the anti-hormonal drug letrozole. These data indicate that the AGR2 pathway represents a novel pro-oncogenic pathway for evaluation as anti-cancer drug developments, especially therapies that by-pass the agonist effects of tamoxifen.
References provided by Crossref.org
Extracellular AGR3 regulates breast cancer cells migration via Src signaling
AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway
AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients