scholarly journals Use of Proton Pump Inhibitors as Adjunct Treatment for Triple-Negative Breast Cancers. An Introductory Study

2014 ◽  
Vol 17 (3) ◽  
pp. 439 ◽  
Author(s):  
Wayne Goh ◽  
Inna Sleptsova-Freidrich ◽  
Nenad Petrovic
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Proton Pump ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Gastric Type ◽  
Dose Dependent

PURPOSE: Triple negative breast cancers (estrogen, progesterone and human epidermal growth factor 2 (HER2) receptor-negative) are among the most aggressive forms of cancers with limited treatment options. Doxorubicin is one of the agents found in many of the current cancer treatment protocols, although its use is limited by dose-dependent cardiotoxicity. This work investigates one of the ways to suppress cancer growth by inhibiting tumor cell ability to remove acid accumulated during its metabolism by proton pump inhibitor esomeprazole (a drug with extensive clinical use) which could serve as an addition to doxorubicin therapy. METHODS: In this work, we have investigated growth suppression of triple-negative breast cancer cells MDA-MB-468 by esomeprazole and doxorubicin by trypan blue exclusion assay. Measurement of acidification of treated cancer cells was performed using intracellular pH-sensitive probe, BCECF-AM. Finally, expression of gastric type proton pump (H+/K+ ATPase, a target for esomeprazole) on MDA-MB-468 cells was detected by immunofluorescence and Western blotting. RESULTS: We have found that esomeprazole suppresses growth of triple-negative breast cancer cell in vitro in a dose-dependent manner through increase in their intracellular acidification. In contrast, esomeprazole did not have significant effect on non-cancerous breast epithelial MCF-10A cells. Esomeprazole increases doxorubicin effects suggesting that dual treatments might be possible. In addition, response of MDA-MB-468 cells to esomeprazole could be mediated by gastric type proton pump (H+/K+ ATPase) in cancer cells contrary to previous beliefs that this proton pump expression is restricted to parietal cells of the stomach epithelia. CONCLUSION: This study provides first evidence that adjunct use of esomeprazole in breast cancer treatment might be a possible to combat adverse effects of doxorubicin and increase its effectiveness. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Hong Luo ◽  
Zhicheng Zhou ◽  
Shan Huang ◽  
Mengru Ma ◽  
Manyu Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Triple Negative Breast Cancer ◽  
Fatty Acid Synthase ◽  
Triple Negative ◽  
Trichostatin A ◽  
Affinity Purification ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Breast Cancers

AbstractFailures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.

scholarly journals HMGA1 Modulates Gene Transcription Sustaining a Tumor Signalling Pathway Acting on the Epigenetic Status of Triple-Negative Breast Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1105 ◽  
Author(s):  
Penzo ◽  
Arnoldo ◽  
Pegoraro ◽  
Petrosino ◽  
Ros ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Transcriptional Activation ◽  
Triple Negative ◽  
Critical Factor ◽  
Regulatory Sequences ◽  
Breast Cancers ◽  
Creb Binding Protein ◽  
Mesenchymal Transition

Chromatin accessibility plays a critical factor in regulating gene expression in cancer cells. Several factors, including the High Mobility Group A (HMGA) family members, are known to participate directly in chromatin relaxation and transcriptional activation. The HMGA1 oncogene encodes an architectural chromatin transcription factor that alters DNA structure and interacts with transcription factors favouring their landing onto transcription regulatory sequences. Here, we provide evidence of an additional mechanism exploited by HMGA1 to modulate transcription. We demonstrate that, in a triple-negative breast cancer cellular model, HMGA1 sustains the action of epigenetic modifiers and in particular it positively influences both histone H3S10 phosphorylation by ribosomal protein S6 kinase alpha-3 (RSK2) and histone H2BK5 acetylation by CREB-binding protein (CBP). HMGA1, RSK2, and CBP control the expression of a set of genes involved in tumor progression and epithelial to mesenchymal transition. These results suggest that HMGA1 has an effect on the epigenetic status of cancer cells and that it could be exploited as a responsiveness predictor for epigenetic therapies in triple-negative breast cancers.

scholarly journals Cytotoxicity of Selenium Immunoconjugates against Triple Negative Breast Cancer Cells

2018 ◽  
Vol 19 (11) ◽  
pp. 3352 ◽  
Author(s):  
Soni Khandelwal ◽  
Mallory Boylan ◽  
Julian Spallholz ◽  
Lauren Gollahon
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cell Growth ◽  
Cell Lines ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Cancer Cell Growth

Within the subtypes of breast cancer, those identified as triple negative for expression of estrogen receptor α (ESR1), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), account for 10–20% of breast cancers, yet result in 30% of global breast cancer-associated deaths. Thus, it is critical to develop more targeted and efficacious therapies that also demonstrate less side effects. Selenium, an essential dietary supplement, is incorporated as selenocysteine (Sec) in vivo into human selenoproteins, some of which exist as anti-oxidant enzymes and are of importance to human health. Studies have also shown that selenium compounds hinder cancer cell growth and induce apoptosis in cancer cell culture models. The focus of this study was to investigate whether selenium-antibody conjugates could be effective against triple negative breast cancer cell lines using clinically relevant, antibody therapies targeted for high expressing breast cancers and whether selenium cytotoxicity was attenuated in normal breast epithelial cells. To that end, the humanized monoclonal IgG1 antibodies, Bevacizumab and Trastuzumab were conjugated with redox selenium to form Selenobevacizumab and Selenotrastuzumab and tested against the triple negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231 as well as a normal, immortalized, human mammary epithelial cell line, HME50-5E. VEGF and HER2 protein expression were assessed by Western. Although expression levels of HER2 were low or absent in all test cells, our results showed that Selenobevacizumab and Selenotrastuzumab produced superoxide (O2•−) anions in the presence of glutathione (GSH) and this was confirmed by a dihydroethidium (DHE) assay. Interestingly, superoxide was not elevated within HME50-5E cells assessed by DHE. The cytotoxicity of selenite and the selenium immunoconjugates towards triple negative cells compared to HME-50E cells was performed in a time and dose-dependent manner as measured by Trypan Blue exclusion, MTT assay and Annexin V assays. Selenobevacizumab and Selenotrastuzumab were shown to arrest the cancer cell growth but not the HME50-5E cells. These results suggest that selenium-induced toxicity may be effective in treating TNBC cells by exploiting different immunotherapeutic approaches potentially reducing the debilitating side effects associated with current TNBC anticancer drugs. Thus, clinically relevant, targeting antibody therapies may be repurposed for TNBC treatment by attachment of redox selenium.

scholarly journals Shikonin promotes ubiquitination and degradation of cIAP1/2-mediated apoptosis and necrosis in triple negative breast cancer cells

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anqi Wang ◽  
Jiayu Liu ◽  
Yuhan Yang ◽  
Zhejie Chen ◽  
Caifang Gao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Enzyme Linked Immunosorbent Assay ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Apoptosis Protein

Abstract Background Shikonin (SKO) is a natural naphthoquinone derived from Chinese herbal medicine Arnebiae Radix with high development potentials due to its anti-inflammatory and anti-tumor activities. Overwhelming evidences have indicated that SKO can induce both necrosis and apoptosis in cancer cells, while the mechanisms for triple negative breast cancer cells is still need to be disclosed. Methods In this study, kinds of molecular biological technologies, including flow-cytometry, Western blot, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA) as well as real-time quantitative PCR (RT-qPCR), were applied for investigation on the underlying mechanisms of SKO induced necrosis and apoptosis for MDA-MB-231 cells. Inhibitors were also used for validation ofthe key signaling pathways involved in SKO triggered necrosis and apoptosis. Results We found that SKO significantly triggered necrosis and apoptosis of MDA-MB-231 cells in both a concentration- and time-dependent manner. Mechanism studies demonstrated that SKO significantly promoted the autoubiquitination levels and facilitated the proteasome dependent degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) and cIAP2 in MDA-MB-231 cells. Autoubiquitination and degradation of cIAP1 and cIAP2 induced by SKO further led to significant decreased ubiquitination and inactivation of RIP1, which played an important role in inhibition of pro-survival and accelerating of necrosis of MDA-MB-231 cells. Treatment with proteasome inhibitor lactacystin significantly rescued the cell viability induced by treatment of SKO. Conclusions Our results demonstrate that SKO promotes the autoubiquitination and degradation of cIAP1 and cIAP2, which further induces the decrease of the ubiquitination of RIP1 to inhibit the activation of pro-survival signaling pathways and accelerate the necrosis of MDA-MB-231 cells. The disclosed mechanisms of SKO induced necrosis and apoptosis in our study is firstly reported, and it is believed that SKO could be considered as a potential candidate and further developed for the treatment of triple negative breast cancer.

scholarly journals Dual Target of EGFR and mTOR Suppress Triple Negative Breast Cancer Cell Growth Via Regulation The Phosphorylation of mTOR Downstream Proteins

2021 ◽  
Author(s):  
Jing Ma ◽  
Hongtao Li ◽  
Yanzhen Cao ◽  
Jingjing Fan ◽  
Binlin Ma
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Model ◽  
Mammalian Target Of Rapamycin ◽  
Alternative Activation ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Breast Cancer Cell Growth ◽  
Mtor Protein

Abstract Background：Triple-negative breast cancers (TNBC) are the most aggressive subtype of breast cancer, accounting for 15% - 20% of all cases, and have no response to available hormonal therapies and anti-HER2-targeted therapies due to the absence of corresponding targets. Over half of TNBC patients have overexpressed EGFR, but they are insensitive to EGFR inhibitors from monotherapy. Mammalian target of rapamycin (mTOR) connected with EGFR in the downstream signaling and involved in the progress of TNBC. The purpose of this study is to determine the combined effect of everolimus and geftinib in a TNBC cell model and investigate the possible mechanism. Results: This work showed the expression EGFR and p-mTOR protein in TNBC tissues were significantly higher than that in non-TNBC(p<0.05), while the expression of mTOR, S6K1, pEGFR and p-S6K1 were significantly higher in the EGF stimulation. EGFR and p-mTOR protein are related to poor prognosis. EGFR inhibitor gefitinib and mTOR inhibitor everolimus significantly inhibited the proliferation of human triple-negative breast cancer MDA-MB-468 cells and arrested cells in G0/G1 phase when applied separately and in combination in a dose-dependent manner (P<0.05). Meanwhile, the rate of apoptosis of MDA-MB-468 cells was significantly incresased separately by two drugs (P<0.01). Furthermore, the combination of everolimus and geftinib reduced the phosphorylation of mTOR downstream proteins. Instead, the phosphorylation of 4E-BP1 was enhanced after the everolimus and geftinib treatment, indicated an alternative activation pattern. Conclusions: These results suggested that dual inhibition of mTOR and EGFR could be a promising approach to treat TNBC.

scholarly journals Targeting Mutated p53 Dependency in Triple-Negative Breast Cancer Cells Through CDK7 Inhibition

2021 ◽  
Vol 11 ◽  
Author(s):  
Jingyu Peng ◽  
Ming Yang ◽  
Ran Bi ◽  
Yueyuan Wang ◽  
Chunxi Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Cell Cycle Progression ◽  
Triple Negative ◽  
P53 Mutation ◽  
Cell Counting ◽  
Dependent Manner ◽  
P53 Expression

BackgroundCyclin-dependent kinase 7 (CDK7) is crucial for cell cycle progression and gene expression transcriptional regulation, which are often not assessed in cancer developing process. CDK7 inhibitors have emerged as promising drugs for treating diverse cancers, including breast cancer. However, the mechanism behind its anticancer effect has not been well investigated. Here, the possible mechanism of CDK7 inhibitors for treating human triple-negative breast cancer (TNBC) has been studied.MethodsThe effects of CDK7 inhibitors on breast cancer cells have been identified by measuring cell viability (Cell Counting Kit-8) and cell proliferation and calculating colony formation. The short hairpin RNA and short interfering RNA were used for the construction of knockdown cells. To assess the expression of associated proteins, western blot was used.ResultsThis study confirmed that, compared to hormone receptor-positive breast cancer cells, TNBC cells were more sensitive to THZ1, a novel CDK7 inhibitor. THZ1 treatment specifically downregulated mutated p53 in a dose- and time-dependent manner in TNBC cells with p53 mutation. Another CDK7 inhibitor, LDC4297, also potently interfered with the expression of mutated p53. Furthermore, endogenous CDK7 expression was positively correlated with the levels of mutated p53 in TNBC cells with p53 mutation. Downregulating mutated p53 expression significantly suppressed the proliferation of TNBC cells with p53 mutation.ConclusionOur findings demonstrated that targeting CDK7 was an effective approach for the treatment of TNBC with p53 mutation.

Improving the efficacy of chemotherapy drugs for the treatment of triple-negative breast cancers.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 107-107
Author(s):  
Behyar Zoghi ◽  
Peter Ravdin
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
High Throughput ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Expression Profiles ◽  
Breast Cancers ◽  
Efficient Treatment ◽  
Chemotherapy Drugs

107 Background: Approximately 15-20% of all breast cancers account for triple-negative breast cancers that exhibit aggressive, distinct metastatic pattern and poor prognosis. More than 50% of patients with triple negative breast cancers develop chemoresistance and do not respond to chemotherapeutic drugs, leading to early relapse and shorter survival. Understanding the mechanisms underlying such resistance is therefore crucial for the development of new, efficacious cancer drugs. Methods: Through high-throughput miRNA inhibitor library screens, we have identified miRNA inhibitors that sensitize resistant triple negative breast cancer cells to paclitaxel, a drug commonly used to treat triple negative breast cancers. Results: Through high-throughput miRNA inhibitor library screens, we have identified miRNA inhibitors that sensitize resistant triple negative breast cancer cells to paclitaxel, a drug commonly used to treat triple negative breast cancers. Since miRNAs are endogenously expressed and can be easily manipulated using synthetic oligoribonucleotides, we believe that they represent more attractive targets than the single gene or gene product that is the target of conventional cancer treatments that are typically prone to drug resistance. Supporting this, we have recently demonstrated that miRNAs can be systemically delivered to treat breast cancer lung metastasis without any hepatotoxicity. In addition to being a potent therapeutic regimen, our preliminary analyses reveal that miRNAs can be bonafide early prognostic markers to monitor treatment response to specific drugs in triple-negative breast cancers. Conclusions: Taken together, these findings suggest that miRNA can serve as potent therapeutic adjuvants and although the data content of miRNA profiles is far less than that of gene expression profiles, by virtue of their ability to modulate entire spectrum of genes and pathways miRNAs have potential to be better classifiers for the prognosis and response to treatment of cancers. We believe that the identification of miRNAs that mediate chemoresistance could lead to more efficient treatment selection at the patient level and an improved response rates at the population level.

scholarly journals BSCI-15. Osteopontin plays a crucial role in invasiveness of triple negative breast cancer cells in the context of human microglia

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii4-iii4
Author(s):  
Kamil Wojnicki ◽  
Agata Kochalska ◽  
Katarzyna Poleszak ◽  
Adria-Jaume Roura ◽  
Ewa Matyja ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Human Microglia

Abstract The triple-negative breast cancer (TNBC) is the most malignant among breast cancers and has the high risk of developing metastasis into the brain. Metastases of breast cancers are increasing and pose a clinical challenge as the current treatments are not effective due to the unique brain microenvironment for metastatic breast cancer cells. While the contribution of brain macrophages to the formation of the metastatic niche is established, factors responsible for the crosstalk between cells remain elusive. SPP1 encoding a secreted phosphoprotein 1 (ostepontin) is highly overexpressed in malignant breast cancers. We evaluated the role of SPP1 in invasion and metastasis of human breast cancer cells. We found the increased invasion of triple-negative MDA-MB-231 (MDA-231) cells in the presence of human microglial HMSV40 cells. Using Western blot analysis demonstrated the elevated levels of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) in MDA-231 cells in co-cultures. Moreover, blocking SPP1 and integrin interactions with the synthetic RGD peptide, efficiently diminished both basic and microglia-induced invasion of MDA-231. To assess the role of SPP1 in cell invasion, we established the MDA-231 cells with knocked-down SPP1 expression using shRNA (shSPP1). Interestingly, the shSPP1 cells were unresponsive towards HMSV40 microglia. We have previously found that an antibiotic minocycline reduces SPP1 expression in glioma cells. We performed cell toxicity studies on 4 breast cancer cell lines and various non-malignant cells. All tested malignant cancer cells were more sensitize to minocycline than non-cancerous cells and breast cancer cells derived from TNBC were the most susceptible. Altogether, we demonstrate that microglia support invasion of breast cancer cells via SPP1/osteopontin triggering the integrin signalling, and minocycline by downregulating SPP1 expression may reduce both basic and microglia-induced cancer invasion. Therefore, we purpose that minocycline could be a new therapeutics targeting metastatic brain cancers.

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