• BMB Reports
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• v.52 no.12
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• pp.706-711
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• 2019

Cisplatin (Cis-DDP) is one of the most widely used anti-cancer drugs. It is applicable to many types of cancer, including lung, bladder, and breast cancer. However, its use is now limited because of drug resistance. p90 ribosomal S6 kinase (p90RSK) is one of the downstream effectors in the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathway and high expression of p90RSK is observed in human breast cancer tissues. Therefore, we investigated the role of p90RSK in the Cis-DDP resistance-related signaling pathway and epithelial-mesenchymal transition (EMT) in breast cancer cells. First, we discovered that MDA-MB-231 cells exhibited more Cis-DDP resistance than other breast cancer cells, including MCF-7 and BT549 cells. Cis-DDP increased p90RSK activation, whereas the inactivation of p90RSK using a small interfering RNA (siRNA) or dominant-negative kinase mutant plasmid overexpression significantly reduced Cis-DDP-induced cell proliferation and migration via the inhibition of matrix metallopeptidase (MMP)2 and MMP9 in MDA-MB-231 cells. In addition, p90RSK activation was involved in EMT via the upregulation of mRNA expression, including that of Snail, Twist, ZEB1, N-cadherin, and vimentin. We also investigated NF-κB, the upstream regulator of EMT markers, and discovered that Cis-DDP treatment led to NF-κB translocation in the nucleus as well as its promoter activity. Our results suggest that targeting p90RSK would be a good strategy to increase Cis-DDP sensitivity in triple-negative breast cancers.

• Laboraroty Animal Research
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• v.34 no.4
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• pp.160-165
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• 2018

Breast cancer remains the second leading cause of cancer death among woman, worldwide, despite advances in identifying novel targeted therapies and the development of treating strategies. Classification of clinical subtypes (ER+, PR+, HER2+, and TNBC (Triple-negative)) increases the complexity of breast cancers, which thus necessitates further investigation. Mouse models used in breast cancer research provide an essential approach to examine the mechanisms and genetic pathway in cancer progression and metastasis and to develop and evaluate clinical therapeutics. In this review, we summarize tumor transplantation models and genetically engineered mouse models (GEMMs) of breast cancer and their applications in the field of human breast cancer research and anti-cancer drug development. These models may help to improve the knowledge of underlying mechanisms and genetic pathways, as well as creating approaches for modeling clinical tumor subtypes, and developing innovative cancer therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4445-4452
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• 2012

Background: Prognosis of breast cancer depends on classic pathological factors and also tumor angiogenesis. This study aimed to evaluate the clinicopathological factors of breast cancer in a tertiary centre with a focus on the relationship between tumor angiogenesis and clinicopathological factors. Methods: Clinicopathological data were retrieved from the archived formal pathology reports for surgical specimens diagnosed as invasive ductal carcinoma, NOS. Microvessels were immunohistochemically stained with anti-CD34 antibody and quantified as microvessel density. Results: At least 50% of 94 cases of invasive breast ductal carcinoma in the study were advanced stage. The majority had poor prognosis factors such as tumor size larger than 50mm (48.9%), positive lymph node metastasis (60.6%), and tumor grade III (52.1%). Higher percentages of estrogen and progesterone receptor negative cases were recorded (46.8% and 46.8% respectively). Her-2 overexpression cases and triple negative breast cancers constituted 24.5% and 22.3% respectively. Significantly higher microvessel density was observed in the younger patient age group (p=0.012). There were no significant associations between microvessel density and other clinicopathological factors (p>0.05). Conclusions: Majority of the breast cancer patients of this institution had advanced stage disease with poorer prognostic factors as compared to other local and western studies. Breast cancer in younger patients might be more proangiogenic.

• Genomics & Informatics
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• v.19 no.2
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• pp.17.1-17.13
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• 2021

Breast cancer is one of the leading causes of cancer in women all over the world and accounts for ~25% of newly observed cancers in women. Epigenetic modifications influence differential expression of genes through non-coding RNA and play a crucial role in cancer regulation. In the present study, epigenetic regulation of gene expression by in-silico analysis of histone modifications using chromatin immunoprecipitation sequencing (ChIP-Seq) has been carried out. Histone modification data of H3K4me3 from one normal-like and four breast cancer cell lines were used to predict miRNA expression at the promoter level. Predicted miRNA promoters (based on ChIP-Seq) were used as a probe to identify gene targets. Five triple-negative breast cancer (TNBC)-specific miRNAs (miR153-1, miR4767, miR4487, miR6720, and miR-LET7I) were identified and corresponding 13 gene targets were predicted. Eight miRNA promoter peaks were predicted to be differentially expressed in at least three breast cancer cell lines (miR4512, miR6791, miR330, miR3180-3, miR6080, miR5787, miR6733, and miR3613). A total of 44 gene targets were identified based on the 3'-untranslated regions of downregulated mRNA genes that contain putative binding targets to these eight miRNAs. These include 17 and 15 genes in luminal-A type and TNBC respectively, that have been reported to be associated with breast cancer regulation. Of the remaining 12 genes, seven (A4GALT, C2ORF74, HRCT1, ZC4H2, ZNF512, ZNF655, and ZNF608) show similar relative expression profiles in large patient samples and other breast cancer cell lines thereby giving insight into predicted role of H3K4me3 mediated gene regulation via the miRNA-mRNA axis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10505-10508
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• 2015

Background: Breast cancer is an important cause of death among women. One way of classifying different forms of breast cancer is by molecular features, usually in terms of the four subtypes: luminal A, luminal B, HER2-enriched, and triple negative. Objectives: This study aimed to investigate the association between molecular subtypes and survival among breast cancer patients treated with radiotherapy. Materials and Methods: A retrospective cohort study was conducted. The subjects were 272 breast cancer patients who had received treatment in the radiotherapy unit at Srinagarind Hospital, Thailand, between 1 January, 1999, and 31 May, 2009. The end of the study was 1 June, 2014. Overall survival was defined as the time elapsing between initial registration at the radiotherapy unit and death or the end of the study. Survival curves were estimated by the Kaplan-Meier method, and a multivariate analysis was performed using Cox's proportional hazard regression model. Results: The patient mean age was $47.5{\pm}10.4$ at the time of diagnosis. Of the 272 patients, 146 (53.7%) were classified as luminal A, 12 (4.4%) as luminal B, 30 (11.0%) as HER2-enriched, and 84 (30.9%) as triple negative. The overall survival rates at 1, 3 and 5 years were 87.1%, 68.4% and 59.2%, respectively. According to molecular subtypes, HER2-enriched patients had the lowest 5-year survival rate (30.0 %, 95%CI: 15.02-46.55). The median follow-up time was 8.37 years. In the Cox model analysis a higher risk of death was found for patients with HER2-enriched ($HR_{adj}=3.34$, 95%CI:1.96-5.67), triple negative ($HR_{adj}=2.17$, 95%CI: 1.44-3.27), and stage IIlB ($HR_{adj}=2.20$, 95%CI: 1.16-4.17) cancers. Conclusions: The worst survival rates were among patients classified as HER2-enriched, triple negative and at stage IIIB. Early detection and an advanced treatment modality are needed to help these patients.

• BMB Reports
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• v.48 no.6
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• pp.342-347
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• 2015

The expression of epidermal growth factor receptor (EGFR) is an important diagnostic marker for triple-negative breast cancer (TNBC) cells, which lack three hormonal receptors: estrogen and progesterone receptors as well as epidermal growth factor receptor 2. EGFR transactivation can cause drug resistance in many cancers including TNBC, but the mechanism underlying this phenomenon is poorly defined. Here, we demonstrate that insulin treatment induces EGFR activation by stimulating the interaction of EGFR with insulin-like growth factor receptor 1 (IGF-1R) in the MDA-MB-436 TNBC cell line. These cells express low levels of EGFR, while exhibiting high levels of IGF-1R expression and phosphorylation. Low-EGFRexpressing MDA-MB-436 cells show high sensitivity to insulinstimulated cell growth. Therefore, unexpectedly, insulin stimulation induced EGFR transactivation by regulating its interaction with IGF-1R in low-EGFR-expressing TNBC cells. [BMB Reports 2015; 48(6): 342-347]

• Biomolecules & Therapeutics
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• v.31 no.5
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• pp.473-483
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• 2023

Many cancers arise from sites of chronic inflammation, which creates an inflammatory microenvironment surrounding the tumor. Inflammatory substances secreted by cells in the inflammatory environment can induce the proliferation and survival of cancer cells, thereby promoting cancer metastasis and angiogenesis. Therefore, it is important to identify the role of inflammatory factors in cancer progression. This review summarizes the signaling pathways and roles of C-reactive protein (CRP) in various cancer types, including breast, liver, renal, and pancreatic cancer, and the tumor microenvironment. Mounting evidence suggests the role of CRP in breast cancer, particularly in triple-negative breast cancer (TNBC), which is typically associated with a worse prognosis. Increased CRP in the inflammatory environment contributes to enhanced invasiveness and tumor formation in TNBC cells. CRP promotes endothelial cell formation and angiogenesis and contributes to the initiation and progression of atherosclerosis. In pancreatic and kidney cancers, CRP contributes to tumor progression. In liver cancer, CRP regulates inflammatory responses and lipid metabolism. CRP modulates the activity of various signaling molecules in macrophages and monocytes present in the tumor microenvironment, contributing to tumor development, the immune response, and inflammation. In the present review, we overviewed the role of CRP signaling pathways and the association between inflammation and cancer in various types of cancer. Identifying the interactions between CRP signaling pathways and other inflammatory mediators in cancer progression is crucial for understanding the complex relationship between inflammation and cancer.

• Radiation Oncology Journal
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• v.26 no.1
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• pp.65-73
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• 2008

Purpose: Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Materials and Methods: Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor(ER), progesterone receptor(PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. Results: There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history(4/14) and bilateral breast cancers(3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2-associated cancers demonstrated more expression of ER-negative(19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors(negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was not a prognostic factor. Conclusion: Breast cancer that occurs in women with a germline BRCA1 or BRCA2 mutations have recognizable immunohistochemical features, which may be useful in identifying individuals that are more likely to carry germline mutations. Although the BRCA1/2 mutation status was not a prognostic factor in Korean women with early-onset breast cancer, more cases with a longer follow-up period are needed for further study.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.4
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• pp.1553-1558
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• 2015

Background: COX-2 has been shown to play an important role in the development of breast cancer and increased expression has been mooted as a poor prognostic factor. The purpose of this study was to investigate the relationship between COX-2 immunohistochemical expression and known predictive and prognostic factors in breast cancer in a routine diagnostic histopathology setting. Materials and Methods: Formalin-fixed paraffin-embedded tumour tissue of 144 no special type (NST) invasive breast carcinomas histologically diagnosed between January 2009 and December 2012 in Hospital Sultanah Bahiyah, Alor Setar, Kedah were immunostained with COX-2 antibody. COX-2 overexpression was analysed against demographic data, hormone receptor status, HER2-neu overexpression, histological grade, tumour size and lymph node status. Results: COX-2 was overexpressed in 108/144 (75%) tumours and was significantly more prevalent (87%) in hormone receptor-positive tumours. There was no correlation between COX-2 overexpression and HER2/neu status. Triple negative cancers had the lowest prevalence (46%) (p<0.05). A rising trend of COX-2 overexpression with increasing age was observed. There was a significant inverse relationship with tumour grade (p<0.05), prevalences being 94%, 83% and 66% in grades 1, 2 and 3 tumours, respectively. A higher prevalence of COX-2 overexpression in smaller size tumours was observed but this did not reach statistical significance. There was no relationship between COX-2 expression and lymph node status. Conclusions: This study did not support the generally held notion that COX-2 overexpression is linked to poor prognosis, rather supporting a role in tumorigenesis. Larger scale studies with outcome data and basic studies on cancer pathogenetic pathways will be required to cast further light on whether COX-2 inhibitors would have clinical utility in cancer prevention or blockage of cancer progression. In either setting, the pathological assessment for COX-2 overexpression in breast cancers would have an important role in the selection of cancer patients for personalized therapy with COX-2 inhibitors.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2465-2472
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• 2015

Background: The Quality Audit (BQA) program of the Breast Surgeons of Australia and New Zealand (NZ) collects data on early female breast cancer and its treatment. BQA data covered approximately half all early breast cancers diagnosed in NZ during roll-out of the BQA program in 1998-2010. Coverage increased progressively to about 80% by 2008. This is the biggest NZ breast cancer database outside the NZ Cancer Registry and it includes cancer and clinical management data not collected by the Registry. We used these BQA data to compare socio-demographic and cancer characteristics and survivals by ethnicity. Materials and Methods: BQA data for 1998-2010 diagnoses were linked to NZ death records using the National Health Index (NHI) for linking. Live cases were followed up to December $31^{st}$ 2010. Socio-demographic and invasive cancer characteristics and disease-specific survivals were compared by ethnicity. Results: Five-year survivals were 87% for Maori, 84% for Pacific, 91% for other NZ cases and 90% overall. This compared with the 86% survival reported for all female breast cases covered by the NZ Cancer Registry which also included more advanced stages. Patterns of survival by clinical risk factors accorded with patterns expected from the scientific literature. Compared with Other cases, Maori and Pacific women were younger, came from more deprived areas, and had larger cancers with more ductal and fewer lobular histology types. Their cancers were also less likely to have a triple negative phenotype. More of the Pacific women had vascular invasion. Maori women were more likely to reside in areas more remote from regional cancer centres, whereas Pacific women generally lived closer to these centres than Other NZ cases. Conclusions: NZ BQA data indicate previously unreported differences in breast cancer biology by ethnicity. Maori and Pacific women had reduced breast cancer survival compared with Other NZ women, after adjusting for socio-demographic and cancer characteristics. The potential contributions to survival differences of variations in service access, timeliness and quality of care, need to be examined, along with effects of comorbidity and biological factors.