MiR‐200c suppresses TGF‐β signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer

Bai, Wen-Dong; Ye, Xingming; Zhang, Mengyao; Zhu, Haijing; Xi, Wenjin; Huang, Xun; Zhao, Jiao; Gu, Bin; Zheng, Guoxu; Yang, An‐Gang; Jia, Lintao

doi:10.1002/ijc.28782

Cited by 154 publications

(138 citation statements)

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“…This miRNA family, in fact, inhibits tumor proliferation, migration, invasion, stemness, and contributes to overcome resistance to standard therapies (21,(27)(28)(29)(30)(31), but its expression has been associated with breast cancer aggressiveness (32,33). Moreover, miR-200 can either increase or reduce the metastatic potential in different TNBC models (34,35).…”

Section: Discussionmentioning

confidence: 99%

miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer

et al. 2016

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Organization of cancer cells into endothelial-like cell-lined structures to support neovascularization and to fuel solid tumors is a hallmark of progression and poor outcome. In triple-negative breast cancer (TNBC), PDGFRb has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of miRNAs as a therapeutic approach to inhibit PDGFRb-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200. In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted and inhibited, respectively, the formation of vascular-like structures in vitro. Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFRb signaling, promoted significant vascular sprouting of TNBC cells, in part, by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFRb through the direct suppression of ZEB1. Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA-MB-231-stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, IHC and immunofluorescence analyses in TNBC specimens indicated that PDGFRb expression marked tumor cells engaged in vascular lacunae. In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFRb, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR-200 to inhibit the process of vascular lacunae formation in TNBC. Cancer Res; 76(18); 5562-72. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer

et al. 2016

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“…In breast cancer, aberrant expression of such miRs as miR-146a, miR-200, miR-34, and miR-489 has been reported to alter cell growth, stemness, apoptosis, migration, and invasion via targeting of proteins involved in those cellular pathways. [12][13][14][15][16] Nonetheless, there are no reports showing miRs' directly targeting p130Cas and thus affecting breast cancer development.…”

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confidence: 99%

Downregulation of microRNA-362-3p and microRNA-329 promotes tumor progression in human breast cancer

Kang

et al. 2015

Cell Death Differ

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p130Cas regulates cancer progression by driving tyrosine receptor kinase signaling. Tight regulation of p130Cas expression is necessary for survival, apoptosis, and maintenance of cell motility in various cell types. Several studies revealed that transcriptional and post-translational control of p130Cas are important for maintenance of its expression and activity. To explore novel regulatory mechanisms of p130Cas expression, we studied the effect of microRNAs (miRs) on p130Cas expression in human breast cancer MCF7 cells. Here, we provide experimental evidence that miR-362-3p and miR-329 perform a tumor-suppressive function and their expression is downregulated in human breast cancer. miR-362-3p and miR-329 inhibited cellular proliferation, migration, and invasion, thereby suppressing tumor growth, by downregulating p130Cas. Ectopic expression of p130Cas attenuated the inhibitory effects of the two miRs on tumor progression. Relative expression levels of miR-362-3p/329 and p130Cas between normal and breast cancer correlated inversely; miR-362-3p/329 expression was decreased, whereas that of p130Cas increased in breast cancers. Furthermore, we showed that downregulation of miR-362-3p and miR-329 was caused by differential DNA methylation of miR genes. Enhanced DNA methylation (according to methylation-specific PCR) was responsible for downregulation of miR-362-3p and miR-329 in breast cancer. Taken together, these findings point to a novel role for miR-362-3p and miR-329 as tumor suppressors; the miR-362-3p/miR-329-p130Cas axis seemingly has a crucial role in breast cancer progression. Thus, modulation of miR-362-3p/miR-329 may be a novel therapeutic strategy against breast cancer. Cell Death and Differentiation (2016) 23, 484-495; doi:10.1038/cdd.2015; published online 4 September 2015 p130Cas/breast cancer anti-estrogen resistance 1 is a member of the Cas (Crk-associated substrate) family of adaptor proteins and has a central role in tyrosine kinasebased signaling related to cell adhesion, migration, cell cycle control, apoptosis, development, and cancer progression.

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“…Joyfully, about the mutant mechanism, researchers newly reported a case that a breast cancer patient harboring an activating EGFR mutation clinically benefiting from EGFR-targeted treatment (Ali et al, 2014). The immune way ADCC (Nahta, 2012) multiple mAbs HER2 internalization (Ben-Kasu et al, 2009) anti-HER2 vaccine Peptide-based/DNA-based/ anti-idiotypic (Cao et al, 2013;Tagliabue and Campiglio, 2014) Trastuzumab mitogenic signaling (Schroeder et al, 2014;Kawajiri et al, 2015) ADCC 188Re-labeled HYNIC-trastuzuma radioactivity dose-dependent fashion (Luo et al, 2015) 64Cu-DOTA-trastuzumab metastatic breast cancer (Mortimer et al, 2014) Trastuzumab resistance Upregulation of HER3 (Nahta, 2012;Brady et al, 2014;Rimawi et al, 2014;Zang et al, 2014;Nam et al, 2015) miRNAs (miRNA-21, miR-7, miR-200c) (Bai et al, 2014;Chen and Bourguignon, 2014;Huynh and Jones, 2014; H E R 2 c o p y n u m b e r / dimerization status Interaction between HER2 and other ERBB (Lee et al, 2015) autophagy (Yeh et al, 2014) Anthracyclines HER2/TOP2A (Fountzilas et al, 2012) S-222611 ERBB family dimmers (Spicer et al, 2015) NCT Increase pCR rates (Shinde et al, 2015) Flotillin reduction of ErbB2-ErbB3 (Asp and Pust, 2014) CC apoptosis/ proliferation (Khan et al, 2015) Taspase1 Cyclins E, A, and B (Dong et al, 2014) Combined therapy Trastuzumab, carboplatin, paclitaxel (Shinde et al, 2015) Trastuzumab, MK-2206 (Hudis et al, 2013) Trastuzumab, lapatinib (Rimawi et al, 2014;Scaltriti et al, 2014;Schroeder et al, 2014) lapatinib , BYL719 (Brady et al, 2014) AZD8931, paclitaxel (Kurata et al, 2014) Hsp90, laptinib ( …”

Section: Other Associated Micromoleculesmentioning

confidence: 99%

“…WenBai et al (2014) referred, trastuzumab resistance was DOI:http://dx.doi.org/10.7314/APJCP.2015.16.7.2591 Recent Progress in HER2 Associated Breast Cancer -a Review characterized by enhanced invasiveness of breast cancer cells with concomitant EMT and elevated TGF-b signaling (Bai et al, 2014).…”

Section: Trastuzumabmentioning

confidence: 99%

“…Now, a new member of the miRNAs come into being in the breast cancer filed, MiR-7 was proved to inhibit HER2D16 cell migration through a mechanism involving suppression of the miR-7 target gene EGFR and sensitize refractory HER2D16 expressing cells to trastuzumab (Huynh and Jones, 2014). Also miR-200c has seen to suppress TGF-b signaling and counteract trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer (Bai et al, 2014).…”

Section: Trastuzumabmentioning

confidence: 99%

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Recent Progress in HER2 Associated Breast Cancer

Wang¹,

Lei²,

Mei³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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MiR‐200c suppresses TGF‐β signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer

Cited by 154 publications

References 37 publications

miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer

miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer

Downregulation of microRNA-362-3p and microRNA-329 promotes tumor progression in human breast cancer

Recent Progress in HER2 Associated Breast Cancer

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