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?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.

Project description:Simple Summary Overexpression of BQ can confer tamoxifen resistance in ER +ve breast cancer. BQ is a variant of NCOR2 spliced through the exclusion of exon 11. SRSF5 is found to be involved in regulating the splicing of NCOR2. A low expression of SRSF5 enhances the chance of excluding exon 11 from mRNA, leading to the production of mRNA translating for BQ. Therefore, a low expression of SRSF5 can enhance BQ expression and, thus, tamoxifen resistance. SRPK1 can alter the activity of SRSF5 for BQ expression. Inhibition of SRPK1 can reduce TAM resistance by suppressing BQ expression in ER +ve breast cancer. Therefore, targeting the upstream pathway of BQ will be a possible strategy for reversing TAM resistance. Abstract About 70% of breast cancer patients are oestrogen receptor-positive (ER +ve). Adjuvant endocrine therapy using tamoxifen (TAM) is an effective approach for preventing local recurrence and metastasis. However, around half of the patients will eventually develop resistance. Overexpression of BQ323636.1 (BQ) is one of the mechanisms that confer TAM resistance. BQ is an alternative splice variant of NCOR2. The inclusion of exon 11 generates mRNA for NCOR2, while the exclusion of exon 11 produces mRNA for BQ. The expression of SRSF5 is low in TAM-resistant breast cancer cells. Modulation of SRSF5 can affect the alternative splicing of NCOR2 to produce BQ. In vitro and in vivo studies confirmed that the knockdown of SRSF5 enhanced BQ expression, and conferred TAM resistance; in contrast, SRSF5 overexpression reduced BQ expression and, thus, reversed TAM resistance. Clinical investigation using a tissue microarray confirmed the inverse correlation of SRSF5 and BQ. Low SRSF5 expression was associated with TAM resistance, local recurrence and metastasis. Survival analyses showed that low SRSF5 expression was associated with poorer prognosis. We showed that SRPK1 can interact with SRSF5 to phosphorylate it. Inhibition of SRPK1 by a small inhibitor, SRPKIN-1, suppressed the phosphorylation of SRSF5. This enhanced the proportion of SRSF5 interacting with exon 11 of NCOR2, reducing the production of BQ mRNA. As expected, SRPKIN-1 reduced TAM resistance. Our study confirms that SRSF5 is essential for BQ expression. Modulating the activity of SRSF5 in ER +ve breast cancer will be a potential approach to combating TAM resistance.

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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