EZH2 Promotes Expansion of Breast Tumor Initiating Cells through Activation of RAF1-β-Catenin Signaling

Chang, Chun Ju; Yang, Jer Yen; Xia, Weiya; Chen, Chun‐Te; Xie, Xiaoming; Chao, Chi-Hong; Woodward, Wendy A.; Hsu, Jung Mao; Hortobágyi, Gabriel N.; Hung, Mien‐Chie

doi:10.1016/j.ccr.2010.10.035

Cited by 366 publications

(357 citation statements)

References 48 publications

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“…Ectopic EZH2 expression increased the stem cell pool in nontumorigenic breast cells, whereas EZH2 down-regulation reduced the breast TIC population in vitro and in xenograft studies. Our data strengthen those from an earlier study showing that EZH2 can promote breast TIC expansion (13) and further demonstrate the consequences of EZH2 levels on breast cancer initiation. EZH2 down-regulation in TN breast cancer cells retarded breast cancer initiation.…”

Section: Discussionsupporting

confidence: 81%

“…From a clinical perspective, blocking EZH2 may prevent or ameliorate breast cancer initiation in women with high EZH2 protein expression levels in their breast epithelium. Despite interest in the association between EZH2 functions, breast TICs, and TN breast cancer (13), the molecular mechanisms underlying the tumorigenic function of EZH2 in this cancer subtype and the relationship to NOTCH1 signaling have not yet been considered. Furthermore, whereas a role for NOTCH1 in breast tumorigenesis has been established in vivo (30), the factors regulating increased NOTCH1 expression and signaling in breast cancer cells are largely unknown (31,32).…”

Section: Discussionmentioning

confidence: 99%

“…In benign breast tissues, elevated levels of EZH2 protein signal future development of breast cancer up to 12 y before diagnosis, indicating that EZH2 up-regulation precedes morphological atypia or carcinoma (12). Recently, EZH2 has been shown to play a role in self-renewal of breast tumor-initiating cells (TICs) (13). However, direct demonstration that EZH2 promotes breast cancer initiation is lacking, and the responsible mechanisms need further investigation.…”

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confidence: 99%

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EZH2 expands breast stem cells through activation of NOTCH1 signaling

González

Moore

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

166

178

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Breast cancer is the second-leading cause of cancer-related deaths in women, but the details of how it begins remain elusive. Increasing evidence supports the association of aggressive triple-negative (TN) breast cancer with heightened expression of the Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) and increased tumorinitiating cells (TICs). However, mechanistic links between EZH2 and TICs are unclear, and direct demonstration of a tumorigenic function of EZH2 in vivo is lacking. Here, we identify an unrecognized EZH2/NOTCH1 axis that controls breast TICs in TN breast carcinomas. EZH2 overexpression increases NOTCH1 expression and signaling, and inhibition of NOTCH1 activity prevents EZH2-mediated stem cell expansion in nontumorigenic breast cells. We uncover a unique role of EZH2 in activating, rather than repressing, NOTCH1 signaling through binding to the NOTCH1 promoter in TN breast cancer cells. EZH2 binding is independent of its catalytic histone H3 lysine 27 methyltransferase activity and of the Polycomb Repressive Complex 2 but corresponds instead to transcriptional activation marks. In vivo, EZH2 knockdown decreases the onset and volume of xenografts derived from TN breast TICs. Conversely, transgenic EZH2 overexpression accelerates mammary tumor initiation and increases NOTCH1 activation in mouse mammary tumor virus-neu mice. Consonant with these findings, in clinical samples, high levels of EZH2 are significantly associated with activated NOTCH1 protein and increased TICs in TN invasive carcinomas. These data reveal a functional and mechanistic link between EZH2 levels, NOTCH1 signaling activation, and TICs, and provide previously unidentified evidence that EZH2 enhances breast cancer initiation.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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EZH2 expands breast stem cells through activation of NOTCH1 signaling

González

Moore

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

166

178

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“…We further demonstrated that HIF1-α inhibited PRC2 activity through transcriptionally repressed PRC2 components, SUZ12 and EED, selectively. In contrast, HIF1-α was able to induce EZH2 mRNA expression, as is consistent with a previous report identifying hypoxic response element in EZH2 promoter (25). Of interest, a recent study has reported that PRC2/H3K27me3 inactivation induces HIF1A mRNA expression in multiple myeloma (54).…”

Section: Discussionsupporting

confidence: 56%

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Mahara

Lee

Feng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Despite the established oncogenic function of Polycomb repressive complex 2 (PRC2) in human cancers, its role as a tumor suppressor is also evident; however, the mechanism underlying the regulation of the paradoxical functions of PRC2 in tumorigenesis is poorly understood. Here we show that hypoxia-inducible factor 1, α-subunit (HIFI-α) is a crucial modulator of PRC2 and enhancer of zeste 2 (EZH2) function in breast cancer. Interrogating the genomic expression of breast cancer indicates high HIF1A activity correlated with high EZH2 expression but low PRC2 activity in triple-negative breast cancer compared with other cancer subtypes. In the absence of HIFIA activation, PRC2 represses the expression of matrix metalloproteinase genes (MMPs) and invasion, whereas a discrete Ezh2 complexed with Forkhead box M1 (FoxM1) acts to promote the expression of MMPs. HIF1-α induction upon hypoxia results in PRC2 inactivation by selective suppression of the expression of suppressor of zeste 12 protein homolog (SUZ12) and embryonic ectoderm development (EED), leading to a functional switch toward Ezh2/FoxM1-dependent induction of the expression of MMPs and invasion. Our study suggests a tumor-suppressive function of PRC2, which is restricted by HIF1-α, and an oncogenic function of Ezh2, which cooperates with FoxM1 to promote invasion in triple-negative breast cancer.

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“…Intriguingly, HIF1-a inhibition on PRC2 does not affect Ezh2, which is consistent with the report of a positive transcriptional regulation of HIF1-a on EZH2 promoter. 6 These findings identified dual antagonistic roles of HIF1-a in determining the activity of Ezh2 in response to hypoxia, and thus the cellular signaling changes leading to aggressive TNBC development.…”

mentioning

confidence: 98%