ZEB1 induces ER-α 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-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 transcription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase (HDAC)1 complex on the ER-α promoter, leading to DNA hypermethylation and the silencing of ER-α. Thus, ectopic ZEB1 downregulates ER-α expression and subsequently attenuates cell growth inhibition by antiestrogens, such as tamoxifen and fulvestrant. Notably, the depletion of ZEB1 by RNA interference causes ER-α promoter demethylation, restores ER-α 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-α protein expression. Moreover, breast tumors that highly express ZEB1 exhibit ER-α 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.

Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer

“…The observations described above by Li's study group (R. K. Li et al, ) are clearly in line with the same evidence from a study by X. Shi, Tang, and Su () that the upregulation of pseudogene PTENP1 causes inhibition of BC cell proliferation and migration (X. Shi et al, ). Besides, the above explanations about the key interactions of PTENP1 with PTEN against breast tumorigenesis agree with the previously reported evidence showing the ceRNA tumor suppressor role of PTENP1/PTEN in other tumors (Qian, Li, Liu, & Liu, ; G. Yu et al, ; J. Zhang, Zhou, et al, ). The miR‐19b has been shown to have oncogenic roles in various types of malignancies, including BC (M. Liu et al, ; Olive et al, ).…”

RETRACTED ARTICLE: Inhibition of ZEB1-AS1 confers cisplatin sensitivity in breast cancer by promoting microRNA-129-5p-dependent ZEB1 downregulation

“…Multi-drug resistance of chemotherapeutic agents prevails as a major hindrance in breast cancer treatment [5]. Meanwhile, reports have credited the involvement of different factors for potentially influencing the chemosensitivity of tumor cells [6][7][8]. MicroRNA (miR) profiles in combination with other vital factors have been demonstrated to be functional in the occurrence of breast cancer [9].…”

“…ZEB1 has been associated with breast cancer progression by promoting EMT, tumorigenesis, and angiogenesis in breast cancer [19,20]. ZEB1 has been identified as a pivotal role in resistance to antiestrogen therapies in breast cancer treatment [8]. Hence, ZEB1 is of key importance in chemotherapeutic resistance in breast cancer therapy [21].…”

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

“…Known mechanisms of resistance to hormone therapies are complex and include epigenetic regulation of ESR1 expression [5,6], ESR1 mutations [7–12], alternative splicing events [3], ESR1 truncation and fusion events [13], post-translational modifications [14,15], alterations in the hormone binding domain [7,16], alter-native recruitment sites within the genome [17], differential recruitment of coregulators [18], feedback loops by ER target genes on expression/activity of ER [19 ● ], downstream actions of ER target genes on growth factor pathways and other signaling networks [20,21 ●● ], influences of the tumor microenvironment [22], and many others (Figure 1). The details of these mechanisms are beyond the scope of this review but have been thoroughly described by others [23,24].…”