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ZEB1 induces ER-? promoter hypermethylation and confers antiestrogen resistance in breast cancer.

ABSTRACT: Antiestrogen resistance is a major obstacle to endocrine therapy for breast cancers. Although reduced estrogen receptor-? (ER-?) expression is a known contributing factor to antiestrogen resistance, the mechanisms of ER-? downregulation in antiestrogen resistance are not fully understood. Here, we report that ectopic zinc-finger E-box binding homeobox 1 (ZEB1) is associated with ER-? deficiency in breast cancer cells and thus confers antiestrogen resistance. Mechanistically, ZEB1 represses ER-? transcription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase (HDAC)1 complex on the ER-? promoter, leading to DNA hypermethylation and the silencing of ER-?. Thus, ectopic ZEB1 downregulates ER-? expression and subsequently attenuates cell growth inhibition by antiestrogens, such as tamoxifen and fulvestrant. Notably, the depletion of ZEB1 by RNA interference causes ER-? promoter demethylation, restores ER-? expression, and increases the responsiveness of breast cancer cells to antiestrogen treatment. By studying specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between ZEB1 and ER-? protein expression. Moreover, breast tumors that highly express ZEB1 exhibit ER-? promoter hypermethylation. Using a nude mouse xenograft model, we further confirmed that the downregulation of ZEB1 expression restores the responsiveness of breast cancer cells to antiestrogen therapy in vivo. Therefore, our findings suggest that ZEB1 is a crucial determinant of resistance to antiestrogen therapies in breast cancer.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5477580 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer.

Zhang Jianbo J Zhou Chen C Jiang Huimin H Liang Lin L Shi Wen W Zhang Quansheng Q Sun Peiqing P Xiang Rong R Wang Yue Y Yang Shuang S

Cell death & disease 20170406 4

Antiestrogen resistance is a major obstacle to endocrine therapy for breast cancers. Although reduced estrogen receptor-α (ER-α) expression is a known contributing factor to antiestrogen resistance, the mechanisms of ER-α downregulation in antiestrogen resistance are not fully understood. Here, we report that ectopic zinc-finger E-box binding homeobox 1 (ZEB1) is associated with ER-α deficiency in breast cancer cells and thus confers antiestrogen resistance. Mechanistically, ZEB1 represses ER-α ...[more]

PMID: 28383555

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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

ZEB1 induces ER-? promoter hypermethylation and confers antiestrogen resistance in breast cancer.

Publications

ZEB1 induces ER-α promoter hypermethylation and confers antiestrogen resistance in breast cancer.

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