Oridonin inhibits VEGF‑A‑associated angiogenesis and epithelial‑mesenchymal transition of breast cancer in�vitro and in�vivo

AbstractCD73 is a cell surface ecto-5′-nucleotidase, which converts extracellular adenosine monophosphate to adenosine. High tumor CD73 expression is associated with poor outcome among triple-negative breast cancer (TNBC) patients. Here we investigated the mechanisms by which CD73 might contribute to TNBC progression. This was done by inhibiting CD73 with adenosine 5′-(α, β-methylene) diphosphate (APCP) in MDA-MB-231 or 4T1 TNBC cells or through shRNA-silencing (sh-CD73). Effects of such inhibition on cell behavior was then studied in normoxia and hypoxia in vitro and in an orthotopic mouse model in vivo. CD73 inhibition, through shRNA or APCP significantly decreased cellular viability and migration in normoxia. Inhibition of CD73 also resulted in suppression of hypoxia-induced increase in viability and prevented cell protrusion elongation in both normoxia and hypoxia in cancer cells. Sh-CD73 4T1 cells formed significantly smaller and less invasive 3D organoids in vitro, and significantly smaller orthotopic tumors and less lung metastases than control shRNA cells in vivo. CD73 suppression increased E-cadherin and decreased vimentin expression in vitro and in vivo, proposing maintenance of a more epithelial phenotype. In conclusion, our results suggest that CD73 may promote early steps of tumor progression, possibly through facilitating epithelial–mesenchymal transition.

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Verminoside from Pseudolysimachion rotundum var. subintegrum sensitizes cisplatin-resistant cancer cells and suppresses metastatic growth of human breast cancer

Scientific Reports ◽

10.1038/s41598-020-77401-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Changhu Lee ◽

Hyung Won Ryu ◽

Sahee Kim ◽

Min Kim ◽

Sei-Ryang Oh ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Metastatic Breast ◽

Human Breast ◽

Mesenchymal Transition ◽

Bioactive Component ◽

Metastatic Growth

AbstractBreast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial–mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.

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TGFβ-induced expression of long noncoding lincRNA Platr18 controls breast cancer axonogenesis

Life Science Alliance ◽

10.26508/lsa.202101261 ◽

2021 ◽

Vol 5 (2) ◽

pp. e202101261

Author(s):

Simon Grelet ◽

Cécile Fréreux ◽

Clémence Obellianne ◽

Ken Noguchi ◽

Breege V Howley ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cell ◽

Tumor Progression ◽

Primary Tumor ◽

Epithelial Mesenchymal Transition ◽

Metastatic Progression ◽

Mesenchymal Transition ◽

Elevated Expression

Metastasis is the leading driver of cancer-related death. Tumor cell plasticity associated with the epithelial–mesenchymal transition (EMT), an embryonic program also observed in carcinomas, has been proposed to explain the colonization of distant organs by the primary tumor cells. Many studies have established correlations between EMT marker expression in the primary tumor and metastasis in vivo. However, the longstanding model of EMT-transitioned cells disseminating to secondary sites is still actively debated and hybrid states are presently considered as more relevant during tumor progression and metastasis. Here, we describe an unexplored role of EMT on the tumor microenvironment by controlling tumor innervation. Using in vitro and in vivo breast tumor progression models, we demonstrate that TGFβ-mediated tumor cell EMT triggers the expression of the embryonic LincRNA Platr18 those elevated expression controls the expression of the axon guidance protein semaphorin-4F and other neuron-related molecules such as IGSF11/VSIG-3. Platr18/Sema4F axis silencing abrogates axonogenesis and attenuates metastasis. Our observations suggest that EMT-transitioned cells are also locally required in the primary tumor to support distant dissemination by promoting axonogenesis, a biological process known for its role in metastatic progression of breast cancer.

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ZBTB7A promotes migration, invasion and metastasis of human breast cancer cells through NF-κB-induced epithelial–mesenchymal transition in vitro and in vivo

The Journal of Biochemistry ◽

10.1093/jb/mvz062 ◽

2019 ◽

Vol 166 (6) ◽

pp. 485-493 ◽

Cited By ~ 5

Author(s):

Anyun Mao ◽

Maojian Chen ◽

Qinghong Qin ◽

Zhijie Liang ◽

Wei Jiang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Cancer Tissue ◽

Mesenchymal Transition ◽

Mcf 7

Abstract It has been generally confirmed that zinc finger and BTB domain containing 7A (ZBTB7A) plays an important role in the occurrence and progression of malignant tumours, but the promotion or inhibition effect is related to tumour type. The mechanism between ZBTB7A and breast cancer is not well understood, so further research is needed. In this study, we first investigated the expression of ZBTB7A in tissue samples of clinical breast cancer patients, MDA-MB-231, MCF-7 and MCF-10A cells. Second, we overexpressed the ZBTB7A in MCF-7 cells and silenced the ZBTB7A in MDA-MB-231 cells using lentivirus transfection technology, respectively, and verified the effect of ZBTB7A on migration and invasion of breast cancer cell lines through in vitro cell function experiments, such as wound-healing assay, migration and invasion assay, quantitative real time reverse transcriptase (qRT-PCR) and western blot. Then, the correlation between the above influences, epithelial–mesenchymal transition (EMT) and NF-κB was analysed. Finally, in vivo tumour transplantation model in nude mice was established to verified the effect of ZBTB7A on metastasis of breast cancer MDA-MB-231 cells. In conclusion, ZBTB7A is highly expressed in cancer tissue, breast cancer cell line MDA-MB-231 and MCF-7. Meanwhile, the high expression of ZBTB7A may promote cell migration, invasion and tumour metastasis, which may be related to EMT events by regulating NF-κB.

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Dark Sweet Cherry (Prunus avium) Anthocyanins Inhibited the Growth and Biomarkers for Breast Cancer Growth and Invasion in Highly Metastatic 4T1 Tumor Cells

Current Developments in Nutrition ◽

10.1093/cdn/nzab036_021 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 279-279

Author(s):

Ana Carolina Silveira Rabelo ◽

Shirley Arbizu ◽

Maria Angelica Miglino ◽

Susanne Talcott ◽

Giuliana Noratto

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Cell Viability ◽

Prunus Avium ◽

Epithelial Mesenchymal Transition ◽

Dose Range ◽

Mesenchymal Transition ◽

4T1 Cells

Abstract Objectives To investigate the mechanisms underlying the breast cancer anti-invasive activity of DSC phenolics enriched in anthocyanins (ACN) in vitro and their potential in vivo. Methods 4T1 cells were treated with ACN extracted from DSC concentrate juice (FruitSmart, Grandview, WA) within dose range 20–80 µg cyanidin 3-glucoside equivalent (C3G)/mL to assess reactive oxygen species (ROS) levels using carboxy-H2DFFDA probe and cell viability using the resazurin kit (Sigma-Aldrich, St Louis, MO). Protein and mRNA expression were investigated using standard procedures and cell migration by wound healing assay. The pilot in vivo study was performed with 4T1 cells orthotopically injected into mammary fat pads of BALB/c mice (Envigo, Houston, TX, USA) (n = 4). After tumor growth, animals were gavaged with ACN (150 mg C3G/kg body weight/day, n = 2) or saline solution (control, n = 2) for one week followed by euthanasia and collection of tumors, lungs, and liver tissues for analyses. Results ACN induced ROS production (up to 5.13-fold of control) and inhibited cell viability by 50% (IC50) at 58.6 µg C3G/mL. The ACN (IC50 dose) treatment downregulated phospho-ERK1/2 and upregulated phospho-p38 proteins, linked to cell growth inhibition and caspase-dependent apoptosis mediated by the increase in cleaved/total caspase-3 protein ratio (∼3-fold of control) and suppression of total PARP (∼0.4-fold of control). ACN also suppressed the Akt/mTOR/CREB pathway that promotes proliferation and invasion. 4T1 cell migration was inhibited by 22%, consistent with the phospho-Src downregulation (down to ∼ 0.25-fold of control), that regulate epithelial-mesenchymal transition. Phospho-ERK1/2 and phospho-CREB were downregulated in mice tumors. This was accompanied by the downregulation of Cenpf mRNA in liver and lungs, which correlates with poor prognosis and metastasis, thus supporting the in vitro findings. Conclusions ACN provides a dietary alternative to fight human breast cancer invasion by incorporating DSC into the diet. More studies are guarantee to help improve the quality of life of breast cancer patients. Funding Sources This work was supported by the Northwest Cherry Growers. The authors thank the support of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Brazil for providing Ana Carolina Silveira Rabelo the scholarship.

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LncRNA FBXL19-AS1 promotes breast cancer cells proliferation and invasion via acting as a molecular sponge to miR-718

Bioscience Reports ◽

10.1042/bsr20182018 ◽

2019 ◽

Vol 39 (4) ◽

Cited By ~ 7

Author(s):

Zhenmin Ding ◽

Pengcheng Ye ◽

Xiaohu Yang ◽

Hongmiao Cai

Keyword(s):

Breast Cancer ◽

Epithelial Mesenchymal Transition ◽

Potential Therapeutic Target ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

Non Coding Rnas ◽

Underlying Mechanisms ◽

Proliferation And Invasion

Abstract Long non-coding RNAs (lncRNAs) have been suggested to serve vital roles in tumor initiation and progression. However, the expression and underlying mechanisms of lncRNA FBXL19-AS1 in breast cancer (BC) remain unclear. In the present study, we found that FBXL19-AS1 expression was significantly up-regulated and correlated with advanced clinical features and poor overall survival of BC patients. Functionally, FBXL19-AS1 inhibition suppressed BC cells proliferation, invasion, and epithelial–mesenchymal transition (EMT) processes in vitro and reduced tumor growth in vivo. In addition, we found that FBXL19-AS1 might function as a ceRNA to sponge miR-718, and miR-718 could rescue the effects of FBXL19-AS1 on BC cells progression. Therefore, these findings suggested that FBXL19-AS1 might serve as an oncogenic lncRNA and promoted BC progression by sponging miR-718, indicating FBXL19-AS1 could serve as a potential therapeutic target for BC treatment.

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miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4

Cell Death and Disease ◽

10.1038/s41419-019-2164-2 ◽

2019 ◽

Vol 10 (12) ◽

Cited By ~ 11

Author(s):

Feiya Du ◽

Ling Yu ◽

Ying Wu ◽

Shuqian Wang ◽

Jia Yao ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Acquired Resistance ◽

Mesenchymal Transition ◽

Dual Specificity ◽

Promising Therapeutic Target

AbstractAcquired resistance to chemotherapy is a major obstacle in breast cancer (BC) treatment. Accumulated evidence has uncovered that microRNAs (miRNAs) are vital regulators of chemoresistance in cancer. Growing studies reveal that miR-137 acts as a suppressor in tumor progression. However, it remains obscure the role of miR-137 in modulating the sensitivity of BC cells to doxorubicin (DOX). In this study, we demonstrate that miR-137 exerts a significant effect on repressing the development of chemoresistance of BC cells in response to DOX via attenuating epithelial-mesenchymal transition (EMT) of tumor cells in vitro and in vivo. MiR-137 overexpression dramatically elevated the sensitivity of BC cells to DOX as well as impaired the DOX-promoted EMT of tumor cells. Mechanistically, miR-137 directly targeted dual-specificity phosphatase 4 (DUSP4) to impact on the EMT and chemoresistance of BC cells upon DOX treatment. Consistently, decreased DUSP4 efficiently enhanced the sensitivity of BC cells to DOX while overexpressed DUSP4 significantly diminished the beneficial effect of miR-137 on BC cells chemoresistance. Moreover, the increased miR-137 heightened the sensitivity of BC cells-derived tumors to DOX through targeting DUSP4 in vivo. Together, our results provide a novel insight into the DOX resistance of BC cells and miR-137 may serve as a new promising therapeutic target for overcoming chemoresistance in BC.

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Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

Cellular Physiology and Biochemistry ◽

10.1159/000479542 ◽

2017 ◽

Vol 42 (5) ◽

pp. 1847-1856 ◽

Cited By ~ 4

Author(s):

Zhi-Dong Lv ◽

Hai-Bo Wang ◽

Xiang-Ping Liu ◽

Li-Ying Jin ◽

Ruo-Wu Shen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Epithelial Mesenchymal Transition ◽

Association Studies ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

Node Metastasis ◽

And Migration

Background/Aims: Epithelial-mesenchymal transition (EMT) is recognized as a crucial mechanism in breast cancer progression and metastasis. Paired-related homeobox 2 (Prrx2) has been identified as a new EMT inducer in cancer, but the underlying mechanisms are still poorly understood. Methods: The expression of Prrx2 was assessed by immunohistochemistry in breast cancer tissues to evaluate the clinicopathological significance of Prrx2, as well as the correlation between Prrx2 and EMT. Short hairpin RNA knockdown of Prrx2 was used to examine cellular effects of Prrx2, detecte the expression of Wnt/β-catenin signaling and EMT-associated proteins, and observe cell proliferation, invasion and migration abilities in vitro and in vivo. Results: Clinical association studies showed that Prrx2 expression was related to tumor size, lymph node metastasis, tumor node metastasis stages, EMT and poor survival. Results also showed that knockdown of Prrx2 could alter cell morphology, suppressed the abilities of cell proliferation, invasion and migration in breast cancer. Moreover, silencing of Prrx2 induced the mesenchymal-epithelial transition and prevented nuclear translocation of β-catenin, inhibited wnt/β-catenin signaling pathway. Conclusion: Our study indicated that Prrx2 may be an important activator of EMT in human breast cancer and it can serve as a molecular target of therapeutic interventions for breast cancer.

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