ERα inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer

Wei, Xiaolong; Dou, Xiaowei; Bai, Junwei; Luo, Xiang‐Qian; Qiu, Siqi; Xi, Didi; Huang, Wen‐He; Du, Chenxing; Man, Kwan; Zhang, Guojun

doi:10.18632/oncotarget.3966

Cited by 25 publications

(26 citation statements)

References 38 publications

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“…42 Moreover, ERα expression was inversely associated with tumour cell EMT and cancer stem-like cell phenotypes. 43,44 In the current study, we found that CRB3 expression was inversely associated with tumour size (Table 1), which is consistent with previous studies showing that downregulation of CRB3 expression induced breast cancer cell proliferation, whereas CRB3 overexpression inhibited proliferation of human breast cell lines. 20,45,46 Our previous study also showed that the downregulation of CRB3 expression increased migration and invasion of breast cancer cells, whereas CRB3 overexpression inhibited migration and invasion of human breast and kidney cancer cell lines.…”

Section: However It Remains To Be Determined How Erα Regulates Crb3supporting

confidence: 92%

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Crumbs protein homolog 3 (CRB3) expression is associated with oestrogen and progesterone receptor positivity in breast cancer

Zhou

et al. 2019

Clin Exp Pharma Physio

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The crumbs protein homolog 3 (CRB3) regulates the tight junction to help maintain epithelial polarity. Altered CRB3 expression was associated with carcinogenesis of epithelial cells. This study detected CRB3 expression in 192 cases of breast cancer tissues and in the Molecular Taxonomy of Breast Cancer International Consortium (Metabric) and The Cancer Genome Atlas (TCGA) datasets for association with triple negative breast cancer (TNBC) phenotypes. The in vitro experiments confirm the ex vivo data. The data showed that levels of both CRB3 mRNA and protein were associated with TNBC phenotypes, ie, 41.1% (39/95) of ER+ breast cancer was CRB3‐positive, whereas 26.9% (25/93) ER– tumour was CRB3‐positive (P = 0.046). Moreover, 47.6% (30/63) of PR+ breast cancer was CRB3‐positive vs 28.4% (33/116) PR‐ tumours positive for CRB3 (P = 0.013). In addition, 40.1% (27/66) of ER+/PR+ tumour was CRB3‐positive, but only 22.4% (19/85) of TNBC showed CRB3 expression (P = 0.048). Indeed, levels of CRB3 mRNA were higher in non‐TNBC than TNBC in both Metabric (P = 3.682e‐10) and TCGA datasets (P = 2.501e‐07). The in vitro data showed that CRB3 expression was higher in luminal (MCF7 and T47D) than in HER2 (MDA‐MB‐453 and SK‐BR‐3) and basal (MDA‐MB‐231 and BT‐549) breast cancer cell lines. More interestingly, ERα regulated expression of CRB3 protein in MCF7 and BT‐549 cells and ERα expression was associated with CRB3 expression in breast cancer tissues specimens. This study demonstrated that ERα could be a novel regulator for CRB3 expression in breast cancer.

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Section: However It Remains To Be Determined How Erα Regulates Crb3supporting

confidence: 92%

“…A previous study reported that ERα expression was negatively associated with the progressive grade of invasive breast cancer . Moreover, ERα expression was inversely associated with tumour cell EMT and cancer stem‐like cell phenotypes …”

Section: Discussionmentioning

confidence: 94%

Crumbs protein homolog 3 (CRB3) expression is associated with oestrogen and progesterone receptor positivity in breast cancer

Zhou

et al. 2019

Clin Exp Pharma Physio

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“…24 These results indirectly suggested that Notch3 can inhibit EMT in breast cancer cells. Unfortunately, the molecular mechanism by which Notch3 inhibits EMT has not been successfully deciphered.…”

Section: Introductionmentioning

confidence: 86%

Notch3 inhibits epithelial–mesenchymal transition by activating Kibra-mediated Hippo/YAP signaling in breast cancer epithelial cells

et al. 2016

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Invasion, metastasis and chemoresistance are leading causes of death in breast cancer patients. A vital change of epithelial cells, epithelial–mesenchymal transition (EMT), is involved in these processes. Unfortunately, the molecular mechanisms controlling EMT remain to be elucidated. Our previous studies have shown that ectopic N3ICD expression inhibits EMT in MDA-MB-231, a triple-negative breast cancer (TNBC) epithelial cell line. To decipher the mechanism, we performed in-depth studies. Specifically, we found that overexpressing N3ICD transcriptionally upregulated the expression of Kibra, an upstream member of the Hippo pathway. Correspondingly, we also observed that phosphorylated Hippo pathway core kinases, including Lats1/2 and MST1/2, were increased and decreased by overexpressing and knocking down Notch3, respectively. Furthermore, we found that the oncogenic transcriptional coactivator yes-associated protein (YAP), which is negatively regulated by the Hippo pathway, was inhibited by overexpressing N3ICD in breast cancer epithelial cells. The ability of Kibra to inhibit EMT has been previously reported. We thus speculated that Notch3 inhibition of EMT is mediated by upregulated Kibra. To verify this hypothesis, a rescue experiment was performed. Evidently, the ability of Notch3 to inhibit EMT can be countered by knocking down Kibra expression. These data suggest that Notch3 inhibits EMT by activating the Hippo/YAP pathway by upregulating Kibra in breast cancer epithelial cells, and Kibra may be a downstream effector of Notch3. These findings deepen our understanding of EMT in both development and disease, and will undoubtedly help to provide new therapeutic strategies for interfering with cancer invasion and metastasis, especially for TNBC.

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“…Furthermore, the expression of ERα negatively correlates with the progressive grade of invasive ductal breast cancer [9]. Moreover, ERα signaling opposes pathways leading to epithelial to mesenchymal transition (EMT) and cancer stem-like cell phenotype [10, 11]. Thus, expression of ERα is connected with less invasive behavior of breast cancer and is considered to be a good indicator of endocrine therapy and breast cancer survival.…”

Section: Introductionmentioning

confidence: 99%

MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ERα Positive Breast Cancer

Lettlová

Brynychová

Blecha

et al. 2018

Cell Physiol Biochem

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Background/Aims: MiRNA-301a-3p is an oncogenic miRNA whose expression is associated with tumor development, metastases and overall poor prognosis. Estrogen receptor α (ERα) is one of the estrogen hormone-activated transcription factors, which regulates a large number of genes and is involved in the mammary gland development. Expression of ERα is considered to be a good indicator for endocrine therapy and breast cancer survival. Loss of ERα in breast cancer patients indicates invasiveness and poor prognosis. In this study, we focus on the regulation of ERα by miR-301a and its role in transition from estrogen-dependent to estrogen-independent breast cancer. Methods: Expression of miR-301a-3p was measured by qRT-PCR in tumor tissue samples from 111 patients with primary breast carcinoma and in mammospheres representing in vitro model of cancer stem-like cells. Dual reporter luciferase assay and complementary experiments were performed to validate ESR1 as a direct target of miR-301a-3p. The effect of miR-301a-3p on estrogen signaling was evaluated on the level of gene and protein expression and growth response to estrogens. Finally, the effect of miR-301a-3p expression on tumor growth was studied in nude mice. Results: We identified ESR1 as a direct target of miR-301a-3p. Ectopic miR-301a-3p causes a decrease in ESR1 mRNA and protein level and modulates the expression of ERα target genes in ERα positive breast cancer cells. Consistently, miR-301a-3p causes a decrease in sensitivity of MCF7 cells to 17β-estradiol and inhibits the growth of estrogen dependent tumor in nude mice. Yet, the mice tumors have significantly increased expression of genes related to cancer stem-like cells and epithelial to mesenchymal transition suggesting enrichment of the population of cells with more invasive properties, in line with our observation that miR-301a-3p expression is highly increased in mammospheres which show a decrease in estrogenic signaling. Importantly, miR-301a-3P level is also increased in primary breast cancer samples exhibiting an ER/PR negative phenotype. Conclusion: Our results confirm ESR1 as a direct target of miR-301a-3p and suggest that miR-301a-3p likely contributes to development of estrogen independence, which leads to a more invasive phenotype of breast cancer.

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ERα inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer

Cited by 25 publications

References 38 publications

Crumbs protein homolog 3 (CRB3) expression is associated with oestrogen and progesterone receptor positivity in breast cancer

Crumbs protein homolog 3 (CRB3) expression is associated with oestrogen and progesterone receptor positivity in breast cancer

Notch3 inhibits epithelial–mesenchymal transition by activating Kibra-mediated Hippo/YAP signaling in breast cancer epithelial cells

MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ERα Positive Breast Cancer

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