• Molecules and Cells
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• v.42 no.9
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• pp.628-636
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• 2019

Altered genetic features in cancer cells lead to a high rate of aerobic glycolysis and metabolic reprogramming that is essential for increased cancer cell viability and rapid proliferation. Pyruvate kinase muscle (PKM) is a rate-limiting enzyme in the final step of glycolysis. Herein, we report that PKM is a potential therapeutic target in triple-negative breast cancer (TNBC) cells. We found that PKM1 or PKM2 is highly expressed in TNBC tissues or cells. Knockdown of PKM significantly suppressed cell proliferation and migration, and strongly reduced S phase and induced G2 phase cell cycle arrest by reducing phosphorylation of the CDC2 protein in TNBC cells. Additionally, knockdown of PKM significantly suppressed $NF-{\kappa}B$ (nuclear factor kappa-light-chain-enhancer of activated B cells) activity by reducing the phosphorylation of p65 at serine 536, and also decreased the expression of $NF-{\kappa}B$ target genes. Taken together, PKM is a potential target that may have therapeutic implications for TNBC cells.

• Biomolecules & Therapeutics
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• v.31 no.6
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• pp.692-699
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• 2023

The lack of molecular targets hampers the treatment of triple-negative breast cancer (TNBC). In this study, we determined the cytotoxicity of domperidone, a dopamine D2 receptor (DRD2) antagonist in human TNBC BT-549 and CAL-51 cells. Domperidone inhibited cell growth in a dose- and time-dependent manner. The annexin V/propidium iodide staining showed that domperidone induced apoptosis. The domperidone-induced apoptosis was accompanied by the generation of mitochondrial superoxide and the down-regulation of cyclins and CDKs. The apoptotic effect of domperidone on TNBC cells was prevented by pre-treatment with Mito-TEMPO, a mitochondria-specific antioxidant. The prevention of apoptosis with Mito-TEMPO even at concentrations as low as 100 nM, implies that the generation of mitochondrial ROS mediated the domperidone-induced apoptosis. Immunoblot analysis showed that domperidone-induced apoptosis occurred through the down-regulation of the phosphorylation of JAK2 and STAT3. Moreover, domperidone downregulated the levels of D2-like dopamine receptors including DRD2, regardless of their mRNA levels. Our results support further development of DRD2 antagonists as potential therapeutic strategy treating TNBC.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.12
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• pp.4863-4867
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• 2015

Background: Triple negative breast cancer (TNBC), characterized as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 Her2 negative and accounting for 10-17% of all breast carcinomas, is only partially responsive to chemotherapy and suffers from a lack of clinically established targeted therapies. The aim of the current study was to evaluate the patterns of treatment and clinicopathology figures in Kurdish patients with triple-negative breast cancer, and to compare these to other reports. Materials and Methods: Between 2001 and 2014, 950 breast cancer patients were referred to our clinic. There were 74 female patients with TNBC, including 70 patients was invasive ductal carcinoma entered into our study. ER and PR positivity was defined as positive immunohistochemical staining in more than 10% of tumor cells. Immunohistochemistry assay with anti-HER2 antibodies was used to identify HER negative (0 and 1+) or positive (2+ and 3+). HER2 gene amplification was determined by fluorescent in situ hybridization (FISH). Overall survival (OS) was plotted with GraphPad Prism 5 Software using Kaplan-Meier and log-rank tests for comparison of results. Results: The mean age in the first diagnosis for 70 patients with triple TNBC and invasive ductal carcinoma was 49.6 years that range of age was 27-82 years. All of the patients were female. Of 70 patients, 23 patients had metastasis. Thirty-two patients (45.7%) were treated with tamoxifen and 39 (55.7%) with radiotherapy. Three-year, 5-year and 10-year OS rates for all patients were 82%, 72% and 64%, respectively. Conclusions: The OS in our West Iran TNBC patients is less than reported elsewhere. However, treatment with combination of tamoxifen plus radiation increases the OS and reduces the mortality rate.

• Journal of Pathology and Translational Medicine
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• v.52 no.6
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• pp.369-377
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• 2018

Background: Chemokine receptor CXC chemokine receptor type 4 (CXCR4) and its ligand CXC motif chemokine 12 (CXCL12; stromal cell-derived factor-1) are implicated in tumor growth, metastasis, and tumor cell-microenvironment interaction. A number of studies have reported that increased CXCR4 expression is associated with worse prognosis in triple-negative breast cancer (TNBC), but its prognostic significance has not been studied in TNBC patients treated with adjuvant chemotherapy. Methods: Two hundred eighty-three TNBC patients who received adjuvant chemotherapy were retrospectively analyzed. Tissue microarray was constructed from formalin-fixed, paraffin-embedded tumor tissue and immunohistochemistry for CXCR4 and CXCL12 was performed. Expression of each marker was compared with clinicopathologic characteristics and outcome. Results: High cytoplasmic CXCR4 expression was associated with younger age (p=.008), higher histologic grade (p=.007) and lower pathologic stage (p=.045), while high CXCL12 expression was related to larger tumor size (p=.045), positive lymph node metastasis (p=.005), and higher pathologic stage (p=.017). The patients with high cytoplasmic CXCR4 experienced lower distant recurrence (p=.006) and better recurrence-free survival (RFS) (log-rank p=.020) after adjuvant chemotherapy. Cytoplasmic CXCR4 expression remained an independent factor of distant recurrence (p=.019) and RFS (p=.038) after multivariate analysis. Conclusions: High cytoplasmic CXCR4 expression was associated with lower distant recurrence and better RFS in TNBC patients treated with adjuvant chemotherapy. This is the first study to correlate high CXCR4 expression to better TNBC prognosis, and the underlying mechanism needs to be elucidated in further studies.

• Molecules and Cells
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• v.46 no.6
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• pp.387-398
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• 2023

Microtubule acetylation has been proposed as a marker of highly heterogeneous and aggressive triple-negative breast cancer (TNBC). The novel microtubule acetylation inhibitors GM-90257 and GM-90631 (GM compounds) cause TNBC cancer cell death but the underlying mechanisms are currently unknown. In this study, we demonstrated that GM compounds function as anti-TNBC agents through activation of the JNK/AP-1 pathway. RNA-seq and biochemical analyses of GM compound-treated cells revealed that c-Jun N-terminal kinase (JNK) and members of its downstream signaling pathway are potential targets for GM compounds. Mechanistically, JNK activation by GM compounds induced an increase in c-Jun phosphorylation and c-Fos protein levels, thereby activating the activator protein-1 (AP-1) transcription factor. Notably, direct suppression of JNK with a pharmacological inhibitor alleviated Bcl2 reduction and cell death caused by GM compounds. TNBC cell death and mitotic arrest were induced by GM compounds through AP-1 activation in vitro. These results were reproduced in vivo, validating the significance of microtubule acetylation/JNK/AP-1 axis activation in the anti-cancer activity of GM compounds. Moreover, GM compounds significantly attenuated tumor growth, metastasis, and cancer-related death in mice, demonstrating strong potential as therapeutic agents for TNBC.

• Genomics & Informatics
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• v.18 no.4
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• pp.35.1-35.7
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• 2020

Identifying the patterns of gene expression in breast cancers is essential to understanding their pathophysiology and developing anticancer drugs. Breast cancer is a heterogeneous disease with different subtypes determined by distinct biological features. Luminal breast cancer is characterized by a relatively high expression of estrogen receptor (ER) and progesterone receptor (PR) genes, which are expressed in breast luminal cells. In ~25% of invasive breast cancers, human epidermal growth factor receptor 2 (HER2) is overexpressed; these cancers are categorized as the HER2 type. Triple-negative breast cancer (TNBC), in which the cancer cells do not express ER/PR or HER2, shows highly aggressive clinical outcomes. TNBC can be further classified into specific subtypes according to genomic mutations and cancer immunogenicity. Herein, we discuss the brief history of TNBC classification and its implications for promising treatments.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.6
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• pp.2577-2581
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• 2014

Background: Triple negative breast cancer is associated with aggressive behavior and high risk of local and regional failure. Aggressive surgical intervention is considered suitable. This makes role of breast conserving therapy (BCT) debatable in these patients. The objective of this study was to compare outcome of BCT for triple negative versus non-triple negative breast cancer. Materials and Methods: Medical records of patients who underwent breast conserving therapy from 1999 to 2009 at Shaukat Khanum Cancer Hospital and had complete receptor status information were extracted. Patients were divided into triple negative breast cancer (TNBC) and non-TNBC. Patient characteristics, medical treatment modalities and adverse events were compared. Expected five year locoregional recurrence free, disease free and overall survival was calculated. The Cox proportional hazard model was used to identify independent predictors of outcome. Results: A total of 194 patients with TNBC and 443 with non-TNBC were compared. Significant difference was present for age at presentation (p<0.0001), family history (p=0.005), grade (p<0.0001) and use of hormonal therapy (p<0.0001). The number of locoregional failures, distant failures and mortalities were not significantly different. No significant difference was present in 5 year locoregional recurrence free (96% vs 92%, p=0.3), disease free (75% vs 74%, p=0.7) and overall survival (78% vs 83%, p=0.2). On multivariate analysis, tumor size, nodal involvement and hormonal treatment were independent predictors of negative events. Conclusions: Breast conserving therapy has comparable outcomes for triple negative and non-triple negative breast cancers.

• Radiation Oncology Journal
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• v.35 no.4
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• pp.332-339
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• 2017

Purpose: This study aimed to evaluate the prognostic effects of lymphovascular invasion (LVI) in triple-negative breast cancer (TNBC) patients who underwent surgical resection. Materials and Methods: A total of 63 non-metastatic TNBC patients who underwent surgical resection were retrospectively investigated from 2007 to 2016 in Inje University Busan Paik Hospital. Pathological tests revealed that 12 patients (19.0%) had LVI. Approximately 61.9% (n = 39) of the patients' samples stained positive for p53. Additional chemotherapy and radiotherapy (RT) were performed in 53 (84.1%) and 47 (74.6%) patients, respectively. Results: The median follow-up period was 39.5 months (range, 5.9 to 123.0 months). The pathological T stage (p = 0.008), N stage (p = 0.014), and p53 positivity (p = 0.044) were associated with LVI. Overall, the 3-year disease-free survival (DFS) rate and overall survival (OS) rate were 85.4% and 90.2%, respectively. Ten patients (15.9%) experienced relapse. LVI (n = 12) was associated with relapses (p = 0.016). p53 positivity was correlated with poor DFS (p = 0.048). Furthermore, LVI was related to poor DFS (p = 0.011) and OS (p = 0.001) and considered as an independent prognostic factor for DFS (p = 0.039). The 3-year DFS of patients with LVI (n = 12) was only 58.3%. Adjuvant RT minimized the negative prognostic effect of LVI on DFS (p = 0.068 [with RT] vs. p = 0.011 [without RT]). Conclusion: LVI was related to the detrimental effects of disease progression and survival of TNBC patients. Thus, a more effective treatment strategy is needed for TNBC patients with LVI.

• Korean Journal of Clinical Oncology
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• v.14 no.2
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• pp.135-141
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• 2018

Purpose: Axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) are important for staging of patients with node-positive breast cancer. However, these can be avoided in select micrometastatic diseases, preventing postoperative complications. The present study evaluated the ability of axillary lymph node maximum standardized uptake value (SUVmax) on positron emission tomography-computed tomography (PET-CT) to predict axillary metastasis of breast cancer. Methods: The records of invasive breast cancer patients who underwent pretreatment (surgery and/or chemotherapy) PET-CT between January 2006 and December 2014 were reviewed. ALNs were preoperatively evaluated by PET-CT. Lymph nodes were dissected by SLNB or ALND. SUVmax was measured in both the axillary lymph node and primary tumor. Student t-test and chi-square test were used to analyze sensitivity and specificity. Receiver operating characteristic (ROC) and area under the ROC curve (AUC) analyses were performed. Results: SUV-tumor (SUV-T) and SUV-lymph node (SUV-LN) were significantly higher in the triple-negative breast cancer (TNBC) group than in other groups (SUV-T: 5.99, P<0.01; SUV-LN: 1.29, P=0.014). The sensitivity (0.881) and accuracy (0.804) for initial ALN staging were higher in fine needle aspiration+PET-CT than in other methods. For PET-CT alone, the subtype with the highest sensitivity (0.870) and negative predictive value (0.917) was TNBC. The AUC for SUV-LN was greatest in TNBC (0.797). Conclusion: The characteristics of SUV-T and SUV-LN differed according to immunohistochemistry subtype. Compared to other subtypes, the true positivity of axillary metastasis on PET-CT was highest in TNBC. These findings could help tailor management for therapeutic and diagnostic purposes.

• Journal of Animal Reproduction and Biotechnology
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• v.38 no.3
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• pp.167-176
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• 2023

Background: A breast cancer is the second leading cause of cancer death in women worldwide and among different types of breast cancers, triple-negative breast cancer (TNBC) has a poor prognosis. Methods: We investigated the potential of ginsenoside compound K (CK), an active ingredient in the bio-transformed ginsenoside, to be used as a therapeutic ingredient by examining the effects of CK on cell proliferation, apoptosis, and cancer-related gene expressions in breast cancer cells. Results: From the results of treating MCF-7, an ER and PR-positive breast cancer cells, and MDA-MB-231 (TNBC) with CK at a concentration of 0-100 µM, the half maximal inhibitory concentration (IC₅₀) values for each cell were 52.17 µM and 29.88 µM, respectively. And also, it was confirmed that cell migration was inhibited above the IC50 concentration. In addition, fluorescence analysis of Apoptosis/Necrosis showed that CK induced apoptosis rather than necrosis of breast cancer cells. Through qPCR, it was confirmed that the expression of genes related to apoptosis and cell cycle arrest was increased in CK-treated breast cancer cells, and it acted more effectively on TNBC. However, the expression of genes related to tumor invasion and metastasis is also increased, so it is necessary to consider the timing of application of CK as a potential therapeutic anticancer compound. Conclusions: CK showed a stronger inhibitory effect in TNBC with poor prognosis but considering the high tumor invasion and metastasis-related gene expression, the timing of application of CK should be considered.