RERG involvement in the RAS pathway and ER-dependent transcription in breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14638-e14638
Author(s):  
Pei-Chen Hsu ◽  
Jar-Yi Ho ◽  
Cheng-Ping Yu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Breast Cancer Cells ◽  
Small Gtpases ◽  
Breast Cancer Cell Lines ◽  
Ras Pathway ◽  
Ras Genes ◽  
Stat3 Signaling ◽  
Luminal Type

e14638 Background: Breast cancer is the highest incidence malignancies in women worldwide. Luminal breast cancers are typically estrogen receptor–positive with better prognosis. However, the rapid disease progression and the high relapse rate of this subtype of breast cancer have become a puzzle in breast cancer treatment. It gave us the motivation to figure out the anomalous molecular mechanism which devoted in. It has been well-documented that the RAS pathway is overloadly activated in more than half of human breast tumors. RAS genes encode a superfamily of small GTPases that contribute to cell growth signals. Methods: Gene expression level were measured by qPCR and Western Blot.Biological effects of each condition were evaluated in cell viability and migration. Results: In this study, we investigated one member of the RAS family, RERG, which was related to the ER pathway and contributed to inhibit Ras activated pathway. Our results showed that knockdown of RERG concomitantly promoted two major oncogenic pathways, Ras and Stat3 signaling pathways, in luminal type breast cancer cell lines. Moreover, ectopic RERG expression significantly inhibited Ras expression. It implicated that RERG mediated in RAS-driven biological effects. Our findings indicated that knockdown of RERG enhanced mobility of the breast cancer cells and made cells more intractable under SERM treatment. Conclusions: We elucidated the tumor-suppressor role of RERG in breast cancer cells though inhibition of the Ras and Stat3 signaling pathways. Therefore, this study might shed light on the important mechanistic insight into the tumorigenesis of ER-positive luminal type cancer and provided the prognostic and therapeutic improved roles of RERG.

Differential involvement of TAK1, RIPK1 and NF-κB signaling in Smac mimetic-induced cell death in breast cancer cells

2019 ◽  
Vol 400 (2) ◽  
pp. 171-180 ◽  
Author(s):  
Nadine Schmidt ◽  
Lisa Kowald ◽  
Sjoerd J.L. van Wijk ◽  
Simone Fulda
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cell Death ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Breast Cancer Cells ◽  
Transforming Growth Factor ◽  
Cancer Therapeutics ◽  
Breast Cancer Cell Lines ◽  
Smac Mimetics

Abstract Smac mimetics (SMs) are considered promising cancer therapeutics. However, the mechanisms responsible for mediating cell death by SMs are still only partly understood. Therefore, in this study, we investigated signaling pathways upon treatment with the bivalent SM BV6 using two SM-sensitive breast cancer cell lines as models. Interestingly, genetic silencing of transforming growth factor (TGF)β activated kinase (TAK)1, an upstream activator of the nuclear factor-kappaB (NF-κB) subunit RelA (p65), increased BV6-induced cell death only in EVSA-T cells, although it reduced BV6-mediated upregulation of tumor necrosis factor (TNF)α in both EVSA-T and MDA-MB-231 cells. By comparison, genetic silencing of p65, a key component of canonical NF-κB signaling, blocked BV6-induced cell death in MDA-MB-231 but not in EVSA-T cells. Similarly, knockdown of NF-κB-inducing kinase (NIK) rescued MDA-MB-231 cells from BV6-induced cell death, while it failed to do so in EVSA-T cells. Consistently, silencing of p65 or NIK reduced BV6-stimulated upregulation of TNFα in MDA-MB-231 cells. In conclusion, TAK1, receptor-interacting kinase 1 (RIPK1) as well as canonical and non-canonical NF-κB signaling are differentially involved in SM-induced cell death in breast cancer cells. These findings contribute to a better understanding of SM-induced signaling pathways.

scholarly journals Novel Nitrogen-Based Chalcone Analogs Provoke Substantial Apoptosis in HER2-Positive Human Breast Cancer Cells via JNK and ERK1/ERK2 Signaling Pathways

2021 ◽  
Vol 22 (17) ◽  
pp. 9621
Author(s):  
Balsam Rizeq ◽  
Ishita Gupta ◽  
Hadeel Kheraldine ◽  
Dana Elkhalifa ◽  
Halema F. Al-Farsi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Chorioallantoic Membrane ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of these two new compounds on human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains nascent. Thus, we herein investigated the effects of these compounds (DK-13 and DK-14) on two HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data revealed that these compounds inhibit cell proliferation, deregulate cell-cycle progression and significantly induce cell apoptosis in both cell lines. Furthermore, the two chalcone compounds cause a significant reduction in the cell invasion ability of SKBR3 and ZR75 cancer cells. In parallel, we found that DK-13 and DK-14 inhibit colony formation of both cell lines in comparison to their matched controls. On the other hand, we noticed that these two compounds can inhibit angiogenesis in the chorioallantoic membrane model. The molecular pathway analysis of chalcone compounds exposed cells revealed that these compounds inhibit the expression of both JNK1/2/3 and ERK1/2, the major plausible molecular pathways behind these events. Our findings implicate that DK-13 and DK-14 possess effective chemotherapeutic outcomes against HER2-positive breast cancer via the ERK1/2 and JNK1/2/3 signaling pathways.

scholarly journals SY-707, an ALK/FAK/IGF1R Inhibitor, Suppresses Growth and Metastasis of Breast Cancer Cells

2021 ◽  
Author(s):  
Ping Liu ◽  
Yinghui Sun ◽  
Shuang Liu ◽  
Jing Niu ◽  
Xijie Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Xenograft Model ◽  
Breast Cancer Cell Lines ◽  
Dependent Manner ◽  
Mouse Xenograft Model

Abstract Background Focal adhesion kinase (FAK), a multi-functional cytoplasmic tyrosine kinase, plays a critical role in cancer migration, proliferation and metastasis via regulating multiple signaling pathways. SY-707 is an ALK/FAK/IGF1R multi-kinase inhibitor and now evaluated in Phase II clinical trial for ALK positive non-small cell lung cancer (NSCLC).MethodsHTRF (Homogeneous Time-Resolved Fluorescence) assay was used to analyze kinase enzyme activity to determine inhibitory activities of SY-707 on other kinases. ATP content, PE-Annexin V and would healing assays were used to examine cell proliferation, cell cycle and migration when cells were treated with SY707. Then, SD rat and beagle dog models were used to evaluate the pharmacokinetics profile, and mouse xenograft model was used to evaluate the in vivo anti-cancer activities of SY707. ResultsIn this study, we assessed preclinical anti-growth and anti-metastasis potency of SY-707 in breast cancer cells. SY-707 was able to inhibit the growth of breast cancer cell lines and induced cell apoptosis by suppressing the FAK signaling pathways. Moreover, SY-707 exerted inhibition on cell migration and adhesion in a dose-dependent manner. In T47D xenograft mice, SY-707 had significant anti-tumor activities lonely or synergistically with Paclitaxel. Meanwhile, SY-707 also displayed significant suppression on spontaneous metastasis of tumor to the lung in 4T1 murine breast cancer xenograft model. ConclusionsSY-707 illustrated potent anti-proliferation and anti-migration potential in breast cancer in vitro and in vivo, implying its therapeutic application for the treatment of breast cancer in future clinical trials.

scholarly journals SY-707, an ALK/FAK/IGF1R Inhibitor, Suppresses Growth and Metastasis of Breast Cancer Cells

2021 ◽  
Author(s):  
Ping Liu ◽  
Yinghui Sun ◽  
Shuang Liu ◽  
Jing Niu ◽  
Xijie Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Xenograft Model ◽  
Breast Cancer Cell Lines ◽  
Dependent Manner ◽  
Mouse Xenograft Model

Abstract Background Focal adhesion kinase (FAK), a multi-functional cytoplasmic tyrosine kinase, plays a critical role in cancer migration, proliferation and metastasis via regulating multiple signaling pathways. SY-707 is an ALK/FAK/IGF1R multi-kinase inhibitor and now evaluated in Phase II clinical trial for ALK positive non-small cell lung cancer (NSCLC).Methods HTRF (Homogeneous Time-Resolved Fluorescence) assay was used to analyze kinase enzyme activity to determine inhibitory activities of SY-707 on other kinases. ATP content, PE-Annexin V and would healing assays were used to examine cell proliferation, cell cycle and migration when cells were treated with SY707. Then, SD rat and beagle dog models were used to evaluate the pharmacokinetics profile, and mouse xenograft model was used to evaluate the in vivo anti-cancer activities of SY707. Results In this study, we assessed preclinical anti-growth and anti-metastasis potency of SY-707 in breast cancer cells. SY-707 was able to inhibit the growth of breast cancer cell lines and induced cell apoptosis by suppressing the FAK signaling pathways. Moreover, SY-707 exerted inhibition on cell migration and adhesion in a dose-dependent manner. In T47D xenograft mice, SY-707 had significant anti-tumor activities lonely or synergistically with Paclitaxel. Meanwhile, SY-707 also displayed significant suppression on spontaneous metastasis of tumor to the lung in 4T1 murine breast cancer xenograft model. Conclusions SY-707 illustrated potent anti-proliferation and anti-migration potential in breast cancer in vitro and in vivo, implying its therapeutic application for the treatment of breast cancer in future clinical trials.

scholarly journals Antiplatelet Therapy Combined with Anastrozole Induces Features of Partial EMT in Breast Cancer Cells and Fails to Mitigate Breast-Cancer Induced Hypercoagulation

2021 ◽  
Vol 22 (8) ◽  
pp. 4153
Author(s):  
Kutlwano R. Xulu ◽  
Tanya N. Augustine
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Antiplatelet Therapy ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines

Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.

scholarly journals Super Magnetic Niosomal Nanocarrier as a New Approach for Treatment of Breast Cancer: A Case Study on SK-BR-3 and MDA-MB-231 Cell Lines

2021 ◽  
Vol 22 (15) ◽  
pp. 7948
Author(s):  
Elham Jamshidifar ◽  
Faten Eshrati Yeganeh ◽  
Mona Shayan ◽  
Mohammad Tavakkoli Yaraki ◽  
Mahsa Bourbour ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cellular Uptake ◽  
Targeted Delivery ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Silica Layer

In the present study, a magnetic niosomal nanocarrier for co-delivery of curcumin and letrozole into breast cancer cells has been designed. The magnetic NiCoFe2O4 core was coated by a thin layer of silica, followed by a niosomal structure, allowing us to load letrozole and curcumin into the silica layer and niosomal layer, respectively, and investigate their synergic effects on breast cancer cells. Furthermore, the nanocarriers demonstrated a pH-dependent release due to the niosomal structure at their outer layer, which is a promising behavior for cancer treatment. Additionally, cellular assays revealed that the nanocarriers had low cellular uptake in the case of non-tumorigenic cells (i.e., MCF-10A) and related high viability but high cellular uptake in cancer cell lines (i.e., MDA-MB-231 and SK-BR-3) and related low viability, which is evidenced in their high cytotoxicity against different breast cancer cell lines. The cytotoxicity of the letrozole/curcumin co-loaded nanocarrier is higher than that of the aqueous solutions of both drugs, indicating their enhanced cellular uptake in their encapsulated states. In particular, NiCoFe2O4@L-Silica-L@C-Niosome showed the highest cytotoxicity effects on MDA-MB-231 and SK-BR-3 breast cancer cells. The observed cytotoxicity was due to regulation of the expression levels of the studied genes in breast cancer cells, where downregulation was observed for the Bcl-2, MMP 2, MMP 9, cyclin D, and cyclin E genes while upregulation of the expression of the Bax, caspase-3, and caspase-9 genes was observed. The flow cytometry results also revealed that NiCoFe2O4@L-Silica-L@C-Niosome enhanced the apoptosis rate in both MDA-MB-231 and SK-BR-3 cells compared to the control samples. The findings of our research show the potential of designing magnetic niosomal formulations for simultaneous targeted delivery of both hydrophobic and hydrophilic drugs into cancer cells in order to enhance their synergic chemotherapeutic effects. These results could open new avenues into the future of nanomedicine and the development of theranostic agents.

scholarly journals Highly expressed SLCO1B3 inhibits the occurrence and development of breast cancer and can be used as a clinical indicator of prognosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tiantian Tang ◽  
Guiying Wang ◽  
Sihua Liu ◽  
Zhaoxue Zhang ◽  
Chen Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines

AbstractThe role of organic anion transporting polypeptide 1B3 (SLCO1B3) in breast cancer is still controversial. The clinical immunohistochemical results showed that a greater proportion of patients with negative lymph nodes, AJCC stage I, and histological grade 1 (P < 0.05) was positively correlated with stronger expression of SLCO1B3, and DFS and OS were also increased significantly in these patients (P = 0.041, P = 0.001). Further subgroup analysis showed that DFS and OS were significantly enhanced with the increased expression of SLCO1B3 in the ER positive subgroup. The cellular function assay showed that the ability of cell proliferation, migration and invasion was significantly enhanced after knockdown of SLCO1B3 expression in breast cancer cell lines. In contrast, the ability of cell proliferation, migration and invasion was significantly reduced after overexpress the SLCO1B3 in breast cancer cell lines (P < 0.05). Overexpression or knockdown of SLCO1B3 had no effect on the apoptotic ability of breast cancer cells. High level of SLCO1B3 expression can inhibit the proliferation, invasion and migration of breast cancer cells, leading to better prognosis of patients. The role of SLCO1B3 in breast cancer may be related to estrogen. SLCO1B3 will become a potential biomarker for breast cancer diagnosis and prognosis assessment.

scholarly journals MicroRNA in combination with HER2-targeting drugs reduces breast cancer cell viability in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lisa Svartdal Normann ◽  
Miriam Ragle Aure ◽  
Suvi-Katri Leivonen ◽  
Mads Haugland Haugen ◽  
Vesa Hongisto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Targeted Treatment ◽  
Breast Cancer Cell Lines ◽  
Altered Expression ◽  
Her2 Breast Cancer

AbstractHER2-positive (HER2 +) breast cancer patients that do not respond to targeted treatment have a poor prognosis. The effects of targeted treatment on endogenous microRNA (miRNA) expression levels are unclear. We report that responsive HER2 + breast cancer cell lines had a higher number of miRNAs with altered expression after treatment with trastuzumab and lapatinib compared to poorly responsive cell lines. To evaluate whether miRNAs can sensitize HER2 + cells to treatment, we performed a high-throughput screen of 1626 miRNA mimics and inhibitors in combination with trastuzumab and lapatinib in HER2 + breast cancer cells. We identified eight miRNA mimics sensitizing cells to targeted treatment, miR-101-5p, mir-518a-5p, miR-19b-2-5p, miR-1237-3p, miR-29a-3p, miR-29c-3p, miR-106a-5p, and miR-744-3p. A higher expression of miR-101-5p predicted better prognosis in patients with HER2 + breast cancer (OS: p = 0.039; BCSS: p = 0.012), supporting the tumor-suppressing role of this miRNA. In conclusion, we have identified miRNAs that sensitize HER2 + breast cancer cells to targeted therapy. This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2 + breast cancers.

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