scholarly journals Metastatic function of METTL18 in breast cancer via actin methylation and Src

2019 ◽  
Author(s):  
Han Gyung Kim ◽  
Ji Hye Kim ◽  
Woo Seok Yang ◽  
Jae Gwang Park ◽  
Yong Gyu Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Actin Polymerization ◽  
Metastatic Potential ◽  
Migration And Invasion ◽  
Intermediate Form ◽  
Breast Cancer Patients ◽  
Set Domain ◽  
Smooth Muscle Contractility

AbstractRecently, a SET domain containing 3 (SETD3) was identified as an actin histidine methyltransferase, functioning to control replication and pathogenesis in multiple mouse models for enterovirus infection as well as the regulation of smooth muscle contractility linked to primary dystocia. Here, in this study, we report another type of actin histidine methyltransferase, METTL18, that regulates the metastatic potential of breast cancer in human. Among methyltransferases, METTL18 was highly amplified in human breast cancer. In particular, poor prognosis was associated with high expression of METTL18 in HER2-negative breast cancer patients. This gene product was also found to be a critical component of metastatic responses. Loss of METTL18 expression significantly reduced metastatic responses of breast tumor cells both in vitro and in vivo. Mechanistically, it was observed that METTL18 increased actin polymerization, upregulated complex formation with HSP90AA1 and Src, enhanced the activity of an intermediate form of Src with tyrosine phosphorylation at both Y416 and Y527, and induced cellular metastatic responses, including morphological change, migration, and invasion of MDA-MB-231 cells in vitro and in mice. Methylated actin at His73 served as a critical site for interaction with HSP90AA1 and Src to activate p85/PI3K and STAT3. Our findings suggest that METTL18 plays critical roles in metastatic responses of HER2-negative breast cancer cells via actin polymerization and the generation of an intermediate form of Src.

scholarly journals A novel long non-coding RNA AC073352.1 promotes metastasis and angiogenesis via interacting with YBX1 in breast cancer

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xue Kong ◽  
Juan Li ◽  
Yanru Li ◽  
Weili Duan ◽  
Qiuchen Qi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Breast Cancer Patients

AbstractBreast cancer is the major cause of cancer death worldwide in women. Patients with metastasis have poor prognosis and the mechanisms of breast cancer metastasis are not completely understood. Long non-coding RNAs (lncRNAs) have been shown to have crucial roles in breast cancer development and progression. However, the underlying mechanisms by which lncRNA-driven breast cancer metastasis are unknown. The main objective of this paper is to explore a functional lncRNA and its mechanisms in breast cancer. Here we identified a novel lncRNA AC073352.1 that was significantly upregulated in breast cancer tissues and was associated with advanced TNM stages and poor prognosis in breast cancer patients. In addition, AC073352.1 was found to promote the migration and invasion of breast cancer cells in vitro and enhance breast cancer metastasis in vivo. Mechanistically, we elucidated that AC073352.1 interacted with YBX1 and stabilized its protein expression. Knock down of YBX1 reduced breast cancer cell migration and invasion and could partially reverse the stimulative effects of AC073352.1 overexpressed on breast cancer metastasis. Moreover, AC073352.1 might be packaged into exosomes by binding to YBX1 in breast cancer cells resulting in angiogenesis. Collectively, our results demonstrated that AC073352.1 promoted breast cancer metastasis and angiogenesis via binding YBX1, and it could serve as a promising, novel biomarker for prognosis and a therapeutic target in breast cancer.

scholarly journals MnTnHex-2-PyP5+, Coupled to Radiation, Suppresses Metastasis of 4T1 and MDA-MB-231 Breast Cancer via AKT/Snail/EMT Pathways

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1769
Author(s):  
Sung-Won Shin ◽  
Changhoon Choi ◽  
Hakyoung Kim ◽  
Yeeun Kim ◽  
Sohee Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast ◽  
Metastatic Potential ◽  
Migration And Invasion ◽  
Tumor Growth Inhibition ◽  
Snail Expression ◽  
Mesenchymal Transition ◽  
4T1 Cells

Tumor migration and invasion induced by the epithelial-to-mesenchymal transition (EMT) are prerequisites for metastasis. Here, we investigated the inhibitory effect of a mimic of superoxide dismutase (SOD), cationic Mn(III) ortho-substituted N-n-hexylpyridylporphyrin (MnTnHex-2-PyP5+, MnHex) on the metastasis of breast cancer in cellular and animal models, focusing on the migration of tumor cells and the factors that modulate this behavior. Wound healing and Transwell migration assays revealed that the migration of mouse mammary carcinoma 4T1 cells was markedly reduced during the concurrent treatment of MnHex and radiation therapy (RT) compared with that of the control and RT alone. Bioluminescence imaging showed that MnHex/RT co-treatment dramatically reduced lung metastasis of 4T1 cells in mice, compared with the sham control and both single treatments. Western blotting and immunofluorescence showed that MnHex treatment of 4T1 cells reversed the RT-induced EMT via inhibiting AKT/GSK-3β/Snail pathway in vitro, thereby decreasing cell migration and invasion. Consistently, histopathological analyses of 4T1 tumors showed that MnHex/RT reduced Snail expression, blocked EMT, and in turn suppressed metastases. Again, in the human metastatic breast cancer MDA-MB-231 cell line, MnHex inhibited metastatic potential in vitro and in vivo and suppressed the RT-induced Snail expression. In addition to our previous studies showing tumor growth inhibition, this study demonstrated that MnHex carries the ability to minimize the metastatic potential of RT-treated cancers, thus overcoming their radioresistance.

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

scholarly journals A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability

Oncogene ◽  
2021 ◽  
Author(s):  
Pengpeng Zhu ◽  
Fang He ◽  
Yixuan Hou ◽  
Gang Tu ◽  
Qiao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
Rapid Expansion ◽  
Breast Cancer Patients ◽  
Coding Region ◽  
Signaling Axis

AbstractThe hostile hypoxic microenvironment takes primary responsibility for the rapid expansion of breast cancer tumors. However, the underlying mechanism is not fully understood. Here, using RNA sequencing (RNA-seq) analysis, we identified a hypoxia-induced long noncoding RNA (lncRNA) KB-1980E6.3, which is aberrantly upregulated in clinical breast cancer tissues and closely correlated with poor prognosis of breast cancer patients. The enhanced lncRNA KB-1980E6.3 facilitates breast cancer stem cells (BCSCs) self-renewal and tumorigenesis under hypoxic microenvironment both in vitro and in vivo. Mechanistically, lncRNA KB-1980E6.3 recruited insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to form a lncRNA KB-1980E6.3/IGF2BP1/c-Myc signaling axis that retained the stability of c-Myc mRNA through increasing binding of IGF2BP1 with m6A-modified c-Myc coding region instability determinant (CRD) mRNA. In conclusion, we confirm that lncRNA KB-1980E6.3 maintains the stemness of BCSCs through lncRNA KB-1980E6.3/IGF2BP1/c-Myc axis and suggest that disrupting this axis might provide a new therapeutic target for refractory hypoxic tumors.

scholarly journals Resveratrol Enhances Inhibition Effects of Cisplatin on Cell Migration and Invasion and Tumor Growth in Breast Cancer MDA-MB-231 Cell Models In Vivo and In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2204
Author(s):  
Meng-Die Yang ◽  
Yang Sun ◽  
Wen-Jun Zhou ◽  
Xiao-Zheng Xie ◽  
Qian-Mei Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Growth ◽  
Cell Viability ◽  
Synergistic Effects ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Tgf Β1

Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (p < 0.05), and increased the expression of E-cadherin (p < 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p < 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.

scholarly journals Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Oncogene ◽  
2021 ◽  
Author(s):  
Francesco Pantano ◽  
Martine Croset ◽  
Keltouma Driouch ◽  
Natalia Bednarz-Knoll ◽  
Michele Iuliani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Osteolytic Lesions ◽  
Cell Colonization

AbstractBone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.

scholarly journals Dual anti-HER2 blockade in late-line treatment of metastatic HER2-positive breast cancer

2021 ◽  
pp. 156-159
Author(s):  
M. A. Frolova ◽  
M. B. Stenina
Keyword(s):  
Breast Cancer ◽  
Treatment Options ◽  
Migration And Invasion ◽  
Line Treatment ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Wide Range ◽  
Positive Breast Cancer

In recent years, there has been a wide range of treatment options for patients with metastatic HER2-positive breast cancer, resulting in  the  highest life expectancy for  these patients among all subtypes. The  addition of  pertuzumab to trastuzumab and docetaxel has been shown to increase overall survival and is therefore recognized as the standard first-line treatment. The most optimal second-line treatment option is trastuzumab emtansine. In  addition, various combinations of  cytostatics and anti HER2 targeting agents can be used. The choice of treatment options in heavily pretreated patients is of great interest. If they have not previously received pertuzumab, is it worth to use it and which combination is the best? One possible option is the combination of eribulin with the dual anti-HER2 blockade with trastuzumab and pertuzumab. Eribulin is an anti-microtubule agent that irreversibly blocks mitosis. In addition, it has non-mitotic effects – in vivo and in vitro experiments demonstrated its ability to restore normal tumor vascularization, reduce the area of hypoxia and, as a consequence, decrease tumor cells migration and invasion. This article represents a clinical case of the use of eribulin with double anti-HER2 blockade in the 6th line of treatment in a patient with metastatic HER2-positive breast cancer. Long-term control of the disease (within 2 years) with a satisfactory quality of life has been demonstrated. 

scholarly journals CircBCBM1 Promotes Breast Cancer Brain Metastasis via miR-125a/BRD4 Axis

2020 ◽  
Author(s):  
Bo Fu ◽  
Wei Liu ◽  
Peng Li ◽  
Li Pan ◽  
Ke Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Breast Cancer Patients ◽  
Breast Cancer Brain Metastasis ◽  
Tumorigenesis And Progression ◽  
And Migration

Abstract Background: Accumulating evidence indicates that circular RNAs (circRNAs) play critical roles in tumorigenesis and progression of various cancers. We previously identified a novel upregulated circRNA, circBCBM1 (hsa_circ_0001944), in the context of breast cancer brain metastasis. However, the potential biological function and molecular mechanism of circBCBM1 in breast cancer brain metastasis remain largely unknown.Methods: In this reserch, we validated the expression and characterization of circBCBM1 through RT-qPCR, Sanger sequencing, RNase R assay and fluorescence in situ hybridization (FISH). Functional experiments were performed to determine the effect of circBCBM1 on growth and metastasis of 231-BR cells both in vitro and in vivo. The regulatory mechanisms among circBCBM1, miR-125a (has-miR-125a-5p), and BRD4 (bromodomain containing 4) were investigated by RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter assay and western blot. Results: Our findings demonstrated that circBCBM1 is a stable and cytoplasmic circRNA. Functionally, silencing of circBCBM1 led to decreased proliferation and migration of 231-BR cells whereas elevated circBCBM1 expression showed reverse effects in vitro. These findings were confirmed in vivo in mouse models, as knockdown of circBCBM1 significantly decreased growth and brain metastases of 231-BR cells. Mechanistically, circBCBM1 functions as an endogenous miR-125a sponge to inhibit miR-125a activity, resulting in the upregulation of BRD4 expression and subsequent upregulation of MMP9 (matrix metallopeptidase 9) through Sonic hedgehog (SHH) signaling pathway. Importantly, circBCBM1 was markedly upregulated in the breast cancer brain metastasis cells and clinical tissue and plasma samples; besides, the overexpression of circBCBM1 in primary cancerous tissues was associated with shorter brain metastasis-free survival (BMFS) of breast cancer patients.Conclusions: These findings indicate that circBCBM1 is involved in breast cancer brain metastasis via circBCBM1/miR-125a/BRD4 axis, which sheds light on the pathogenic mechanism of circBCBM1 and provides translational evidence that circBCBM1 may serve as a novel diagnostic or prognostic biomarker and potential therapeutic target for breast cancer brain metastasis.

CircRNA circ-ERBB2 elevates Warburg effect and facilitates triple-negative breast cancer growth by the miR-136-5p/PDK4 axis

2021 ◽  
Author(s):  
Yihong Huang ◽  
Shuo Zheng ◽  
Ying Lin ◽  
Liming Ke
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Warburg Effect ◽  
Triple Negative ◽  
Pyruvate Dehydrogenase Kinase ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Loss Of Function

Triple negative breast cancer (TNBC) is an aggressive histological subtype of breast cancer. It has been reported that that circRNA circ-ERBB2 (circBase ID: hsa_circ_0007766) is mainly distributed in the cytoplasm of TNBC cells and promotes the proliferation and invasion of TNBC cells. This study aimed to explore the molecular mechanism of circ-ERBB2 regulating the progression of TNBC. Expression of circ-ERBB2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Loss-of-function experiments were performed to investigate the function of circ-ERBB2 in TNBC cells in vitro and in vivo . The regulatory mechanism of circ-ERBB2 was surveyed by bioinformatics analysis, dual-luciferase reporter and RNA immunoprecipitation (RIP) or RNA pull-down assays. We observed that Circ-ERBB2 was overexpressed in TNBC, and TNBC patients with high circ-ERBB2 expression had a poor prognosis. Functionally, circ-ERBB2 knockdown constrained TNBC growth in vivo and reduced Warburg effect, accelerated apoptosis, repressed proliferation, migration, and invasion of TNBC cell in vitro . Mechanically, circ-ERBB2 sponged miR-136-5p to elevate pyruvate dehydrogenase kinase 4 (PDK4) expression. In conclusion, circ-ERBB2 facilitated Warburg effect and malignancy of TNBC cells by the miR-136-5p/PDK4 pathway, at least in part. This study supported circ-ERBB2 as a prognostic indicator for TNBC.

scholarly journals Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer

2020 ◽  
Vol 21 (8) ◽  
pp. 2974 ◽  
Author(s):  
Yasmin M. Attia ◽  
Samia A. Shouman ◽  
Salama A. Salama ◽  
Cristina Ivan ◽  
Abdelrahman M. Elsayed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Volume ◽  
Apoptotic Cell ◽  
Therapy Resistance ◽  
Tamoxifen Treatment ◽  
Clinical Samples ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients

Cyclin-dependent kinase (CDK)-7 inhibitors are emerging as promising drugs for the treatment of different types of cancer that show chemotherapy resistance. Evaluation of the effects of CDK7 inhibitor, THZ1, alone and combined with tamoxifen is of paramount importance. Thus, in the current work, we assessed the effects of THZ1 and/or tamoxifen in two estrogen receptor-positive (ER+) breast cancer cell lines (MCF7) and its tamoxifen resistant counterpart (LCC2) in vitro and in xenograft mouse models of breast cancer. Furthermore, we evaluated the expression of CDK7 in clinical samples from breast cancer patients. Cell viability, apoptosis, and genes involved in cell cycle regulation and tamoxifen resistance were determined. Tumor volume and weight, proliferation marker (Ki67), angiogenic marker (CD31), and apoptotic markers were assayed. Bioinformatic data indicated CDK7 expression was associated with negative prognosis, enhanced pro-oncogenic pathways, and decreased response to tamoxifen. Treatment with THZ1 enhanced tamoxifen-induced cytotoxicity, while it inhibited genes involved in tumor progression in MCF-7 and LCC2 cells. In vivo, THZ1 boosted the effect of tamoxifen on tumor weight and tumor volume, reduced Ki67 and CD31 expression, and increased apoptotic cell death. Our findings identify CDK7 as a possible therapeutic target for breast cancer whether it is sensitive or resistant to tamoxifen therapy.

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