In vitro antineoplastic activity in triple-negative breast cancer cell line and in vivo
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ABSTRACT:
SUBMITTER: Madeira K
PROVIDER: S-EPMC4204317 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
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Project description:Due to its intricate heterogeneity, high invasiveness, and poor prognosis, triple-negative breast cancer (TNBC) stands out as the most formidable subtype of breast cancer. At present, chemotherapy remains the prevailing treatment modality for TNBC, primarily due to its lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth receptor 2 (HER2). However, clinical chemotherapy for TNBC is marked by its limited efficacy and a pronounced incidence of adverse effects. Consequently, there is a pressing need for novel drugs to treat TNBC. Given the rich repository of diverse natural compounds in traditional Chinese medicine, identifying potential anti-TNBC agents is a viable strategy. This study investigated lasiokaurin (LAS), a natural diterpenoid abundantly present in Isodon plants, revealing its significant anti-TNBC activity both in vitro and in vivo. Notably, LAS treatment induced cell cycle arrest, apoptosis, and DNA damage in TNBC cells, while concurrently inhibiting cell metastasis. In addition, LAS effectively inhibited the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and signal transducer and activator of transcription 3 (STAT3), thus establishing its potential for multitarget therapy against TNBC. Furthermore, LAS demonstrated its ability to reduce tumor growth in a xenograft mouse model without exerting detrimental effects on the body weight or vital organs, confirming its safe applicability for TNBC treatment. Overall, this study shows that LAS is a potent candidate for treating TNBC.
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Project description:Nutrient deprivation strategies have been proposed as an adjuvant therapy for cancer cells due to their increased metabolic demand. We examined the specific inhibitory effects of amino acid deprivation on the metastatic phenotypes of the human triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and Hs 578T, as well as the orthotopic 4T1 mouse TNBC tumor model. Among the 10 essential amino acids tested, methionine deprivation elicited the strongest inhibitory effects on the migration and invasion of these cancer cells. Methionine deprivation reduced the phosphorylation of focal adhesion kinase, as well as the activity and mRNA expression of matrix metalloproteinases MMP-2 and MMP-9, two major markers of metastasis, while increasing the mRNA expression of tissue inhibitor of metalloproteinase 1 in MDA-MB-231 cells. Furthermore, methionine restriction downregulated the metastasis-related factor urokinase plasminogen activatior and upregulated plasminogen activator inhibitor 1 mRNA expression. Animals on the methionine-deprived diet showed lower lung metastasis rates compared to mice on the control diet. Taken together, these results suggest that methionine restriction could provide a potential nutritional strategy for more effective cancer therapy.
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Project description:Tumor necrosis factor alpha (TNF-?) is a pro-inflammatory cytokine involved in the promotion and progression of cancer, including triple negative breast cancer cells. Thus, there is significant interest in understanding the molecular signaling pathways that connect TNF-? with the survival of tumor cells. In our experiments, we used as an in vitro model for triple negative breast cancer the cell line Hs578T. The purpose of this study is to determine the gene expression profiling of apoptotic signaling networks after blocking TNF-? formation by using specially designed siRNA molecules to target TNF-? messenger RNA. Knockdown of TNF-? gene was associated with cell proliferation inhibition and apoptosis, as observed by monitoring the cell index using the xCELLigence RTCA System and flow cytometry. PCR array technology was used to examine the transcript levels of 84 genes involved in apoptosis. 15 genes were found to be relevant after comparing the treated group with the untreated one of which 3 were down-regulated and 12 up-regulated. The down-regulated genes are all involved in cell survival, whereas the up-regulated ones are involved in and interact with pro-apoptotic pathways. The results described here indicate that the direct target of TNF-? in the Hs578T breast cancer cell line increases the level of certain pro-apoptotic factors that modulate different cellular networks that direct the cells towards death.
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Project description:PurposeThis study aimed to validate the synergistic effect of ABT-737 on docetaxel using MDA-MB-231, a triple negative breast cancer (TNBC) cell line overexpressing B-cell lymphoma-2 (Bcl-2).MethodsWestern blot analysis was performed to assess expression levels of Bcl-2 family proteins and caspase-related molecules. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle distribution was determined by flow cytometry analysis. Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk) was used for pretreatment to assess the role of caspases.ResultsCell viability of MDA-MB-231 after combination treatment with ABT-737 and docetaxel was significantly lower than that after docetaxel or ABT-737 monotherapy based on MTT assay (both P < 0.001), with a combination index of 0.41. The proportion of sub-G1 population after combination treatment was significantly higher than that after docetaxel or ABT-737 monotherapy (P = 0.001, P = 0.003, respectively). Pretreatment with z-VAD-fmk completely restored cell viability of MDA-MB-231 from apoptotic cell death induced by combination therapy (P = 0.001). Although pro-caspase-8 or Bid did not show significant change in expression level, pro-casepase-9 showed significantly decreased expression after combination treatment. Cleaved caspase-3 showed increased expression while poly (ADP-ribose) polymerase cleavage was induced after combination treatment. However, hypoxia-inducible factor 1-alpha and aldehyde dehydrogenase 1 totally lost their expression after combination treatment.ConclusionCombination of ABT-737 with docetaxel elicits synergistic therapeutic effect on MDA-MB-231, a TNBC cell line overexpressing Bcl-2, mainly by activating the intrinsic pathway of apoptosis. Therefore, adjunct of ABT-737 to docetaxel might be a new therapeutic option to overcome docetaxel resistance of TNBCs overexpressing Bcl-2.
| S-EPMC6204323 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is the most lethal form of breast cancer. Lacking effective therapeutic options hinders treatment of TNBC. Here, we show that bepridil (BPD) and trifluoperazine (TFP), which are FDA-approved drugs for treatment of schizophrenia and angina respectively, inhibit Akt-pS473 phosphorylation and promote FOXO3 nuclear localization and activation in TNBC cells. BPD and TFP inhibit survival and proliferation in TNBC cells and suppress the growth of TNBC tumors, whereas silencing FOXO3 reduces the BPD- and TFP-mediated suppression of survival in TNBC cells. While BPD and TFP decrease the expression of oncogenic c-Myc, KLF5, and dopamine receptor DRD2 in TNBC cells, silencing FOXO3 diminishes BPD- and TFP-mediated repression of the expression of these proteins in TNBC cells. Since c-Myc, KLF5, and DRD2 have been suggested to increase cancer stem cell-like populations in various tumors, reducing these proteins in response to BPD and TFP suggests a novel FOXO3-dependent mechanism underlying BPD- and TFP-induced apoptosis in TNBC cells.
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Project description:There is no effective clinical therapy for triple-negative breast cancers (TNBCs), which have high low-density lipoprotein (LDL) requirements and express relatively high levels of LDL receptors (LDLRs) on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel-cholesterol complex (PTX-CH Emul) was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231) and non-TNBC (MCF7) cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native LDL. The findings of this paper further confirm the therapeutic potential of PTX-CH Emul in clinical applications involving TNBC therapy.
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Project description:ObjectiveAfrican American women with breast cancer experience disproportionately poor survival outcomes, primarily due to the high prevalence of the deadliest subtype; triple-negative breast cancer (TNBC). The CRYβB2 gene is upregulated in tumors from African American patients across all breast cancer subtypes, including TNBC, and is associated with worse survival rates. This study investigated the effect of CRYβB2 on the invasion of TNBC cells and the underlying mechanisms contributing to this phenotype.ResultsWe utilized the SUM159 cells with stable CRYβB2 overexpression in a 3D-culture tumor spheroids model in our investigation. A quantitative 3D invasion assay demonstrated that CRYβB2 overexpression significantly enhanced invasion (median invasion %; SUM159 = 0.14 and SUM159 + CRYβB2 = 0.33). RNA sequencing analysis indicated that CRYβB2 overexpression modulated cell-cell adhesion and extracellular matrix organization pathways, which are critical to invasion of cancer cells. Specifically, CRYβB2 suppressed the expression of key cell-cell adhesion genes known as clustered protocadherins and promoted the expression of PCDH7, a nonclustered protocadherin with known oncogenic roles in various cancers. Notably, the knockout of PCDH7 diminished the invasive capacity induced by CRYβB2 (median invasion %; SUM159 = 0.093, SUM159 + CRYβB2 = 0.184 and SUM159 + CRYβB2/PCDH7-/-=0.082). These findings provide a novel link between a previously identified differentially expressed gene, CRYβB2, in driving breast cancer phenotypes by modulating a class of adhesion proteins.
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Project description:The tumor suppressor menin has dual functions, acting either as a tumor suppressor or as an oncogene/oncoprotein, depending on the oncological context. Triple-negative breast cancer (TNBC) is characterized by lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 and is often a basal-like breast cancer. TNBC is associated with a dismal prognosis and an insufficient response to chemotherapies. Previously, menin was shown to play a proliferative role in ER-positive breast cancer; however, functions of menin in TNBC remains unknown. We have demonstrated that menin is expressed in various TNBC subtypes with the strongest menin expression in the TNBC Hs 578T cells. Depletion of menin by antisense oligonucleotide inhibited cell proliferation, enhanced apoptosis, and induced cell cycle arrest in Hs 578T cells, highlighting oncogenic functions of menin in this TNBC model. To better understand the menin function, we performed AP-MS (Affinity Purification-Mass Spectrometry) using specific antibody against menin. Analysis of menin interactome suggested that menin could drive TNBC tumorigenesis through regulation of the MLL/KMT2A-driven transcriptional activity, mRNA 3’ end processing and apoptosis.
2021-09-10 | PXD024176 | Pride
Project description:Oncogene c-Src has been found to be a potential target for the treatment of triple-negative breast cancer (TNBC). However, the therapeutic effects of the c-Src inhibitor on TNBC patients are controversial compared to those on cell lines. The molecular mechanisms of the inhibitory effects of the c-Src inhibitor on TNBC remain unclear. Herein, we showed that a specific c-Src inhibitor, PP2, was effective in inhibiting phosphorylation of c-Src in 4 cell lines: T-47D, SK-BR-3, SUM1315MO2, and MDA-MB-231, regardless of hormone receptors and human epidermal growth factor receptor 2 (HER2) expression levels. Giving PP2 preferentially reduced the S phase of cell cycles and inhibited colony formation in SUM1315MO2 and MDA-MB-231, but not in SK-BR-3 and T-47D cells. Furthermore, PP2 effectively blocked cell migration/invasion and epithelial-mesenchymal transition (EMT) in TNBC cell lines, SUM1315MO2 and MDA-MB-231. An EMT biomarker, vimentin, was highly expressed in 2 TNBC cell lines when they were compared with SK-BR-3 and T-47D cells. Further depletion of vimentin by shRNA remarkably attenuated the inhibitory effects of the c-Src inhibitor on TNBC cells in vitro and in vivo, indicating a crucial action of vimentin to affect the function of c-Src in TNBC. This study provides an important rationale for the clinic to precisely select TNBC patients who would benefit from c-Src inhibitor treatment. This finding suggests that traditional markers for TNBC are not sufficient to precisely define this aggressive type of cancer. Vimentin is identified as an important biomarker to enable categorization of TNBC.
| S-EPMC5980174 | biostudies-literature
Project description:BACKGROUND:Triple-negative breast cancers (BC) represent a heterogeneous subtype of BCs, generally associated with an aggressive clinical course and where targeted therapies are currently limited. Target validation studies for all BC subtypes have largely employed established BC cell lines, which have proven to be effective tools for drug discovery. RESULTS:Given the lines of evidence suggesting that BC cell lines are effective tools for drug discovery, we assessed the similarities between triple-negative BCs and cell lines, to identify in vitro representatives, modelling the diversity within this BC subtype. 25 BC cell lines, enriched for those lacking ER, PR and HER2 expression, were subjected to transcriptomic, genomic and epigenomic profiling analyses and comparisons were made to existing knowledge of corresponding perturbations in triple-negative BCs. Transcriptional analysis segregated ER-negative BC cell lines into three groups, displaying distinctive abundances for genes involved in epithelial-mesenchymal transition, apocrine and high-grade carcinomas. DNA copy number aberrations of triple-negative BCs were well represented in cell lines and genes with coordinately altered gene expression showed similar patterns in tumours and cell lines. Methylation events in triple-negative BCs were mostly retained in epigenomes of cell lines. Combined methylation and gene expression analyses revealed a subset of genes characteristic of the Claudin-low BC subtype, exhibiting epigenetic-regulated gene expression in BC cell lines and tumours, suggesting that methylation patterns are likely to underpin subtype-specificity. CONCLUSION:Here, we provide a comprehensive analysis of triple-negative BC features on several molecular levels in BC cell lines, thereby creating an in-depth resource to access the suitability of individual lines as experimental models for studying BC tumour biology, biomarkers and possible therapeutic targets in the context of preclinical target validation.
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