Dataset Information

?EF1 down-regulates ER-? expression and confers tamoxifen resistance in breast cancer.

ABSTRACT: Resistance to tamoxifen therapy represents a major barrier to the successful treatment of breast cancer, where a loss of or reduced ER-? level is considered a primary mechanism. Understanding how ER-? expression is regulated would provide insights into new intervention points to overcome tamoxifen resistance. In this study, we report that the expression of ?EF1 is up-regulated by 17?-estradiol (E2) in MCF-7 cells in an ER-?-dependent manner, through either PI3K or NF-?B pathway. Ectopic expression of ?EF1 in turn repressed ER-? transcription by binding to the E(2)-box on the ER-? promoter. At the tissue level of breast cancer, there is a strong and inverse correlation between the expression levels of ?EF1 and ER-?. In MCF-7 cells, an elevated expression of ?EF1 made the cells less sensitive to tamoxifen treatment, whereas overexpression of ER-? compromised the effects of ?EF1 and restored the sensitivity. Also, depletion of ?EF1 by RNA interference in MDA-MB-231 cells restored the expression of ER-? and tamoxifen sensitivity. In conclusion, we have identified an important role of ?EF1 in the development of tamoxifen resistance in breast cancer. Inhibiting ?EF1 to restore ER-? expression might represent a potential therapeutic strategy for overcoming endocrine resistance in breast cancer.

SUBMITTER: Guo S

PROVIDER: S-EPMC3528679 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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δEF1 down-regulates ER-α expression and confers tamoxifen resistance in breast cancer.

Guo Shaocong S Li Yaqing Y Tong Qi Q Gu Feng F Zhu Tianhui T Fu Li L Yang Shuang S

PloS one 20121221 12

Resistance to tamoxifen therapy represents a major barrier to the successful treatment of breast cancer, where a loss of or reduced ER-α level is considered a primary mechanism. Understanding how ER-α expression is regulated would provide insights into new intervention points to overcome tamoxifen resistance. In this study, we report that the expression of δEF1 is up-regulated by 17β-estradiol (E2) in MCF-7 cells in an ER-α-dependent manner, through either PI3K or NF-κB pathway. Ectopic expressi ...[more]

PMID: 23285017

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Project description:The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity-an in vitro metric of tumorigenicity-of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.

Dataset Information

?EF1 down-regulates ER-? expression and confers tamoxifen resistance in breast cancer.

Publications

δEF1 down-regulates ER-α expression and confers tamoxifen resistance in breast cancer.

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