• Biomolecules & Therapeutics
• /
• v.24 no.1
• /
• pp.62-66
• /
• 2016

Amygdalin, D-mandelonitrile-${\beta}$-D-glucoside-6-${\beta}$-glucoside, belongs to aromatic cyanogenic glycoside group derived from rosaceous plant seed. Mounting evidence has supported the anti-cancer effects of amygdalin. However, whether amygdalin indeed acts as an anti-tumor agent against breast cancer cells is not clear. The present study aimed to investigate the effect of amygdalin on the proliferation of human breast cancer cells. Here, we show that amygdalin exerted cytotoxic activities on estrogen receptors (ER)-positive MCF7 cells, and MDA-MB-231 and Hs578T triple-negative breast cancer (TNBC) cells. Amygdalin induced apoptosis of Hs578T TNBC cells. Amygdalin downregulated B-cell lymphoma 2 (Bcl-2), upregulated Bcl-2-associated X protein (Bax), activated of caspase-3 and cleaved poly ADP-ribose polymerase (PARP). Amygdalin activated a pro-apoptotic signaling molecule p38 mitogen-activated protein kinases (p38 MAPK) in Hs578T cells. Treatment of amygdalin significantly inhibited the adhesion of Hs578T cells, in which integrin ${\alpha}5$ may be involved. Taken together, this study demonstrates that amygdalin induces apoptosis and inhibits adhesion of breast cancer cells. The results suggest a potential application of amygdalin as a chemopreventive agent to prevent or alleviate progression of breast cancer, especially TNBC.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.10
• /
• pp.6013-6017
• /
• 2013

Background: To evaluate the clinicopathologic and demographic characteristics of triple-negative breast cancer (TNBC) patients and to determine differences from non-triple-negative cases. Materials and Methods: A detailed review of the medical records of 882 breast cancer (BC) patients was conducted to obtain information regarding age, menopausal status, height and weight at the time of diagnosis, presence of diabetes or hypertension, and pathologic characteristics of the tumor (tumor size, lymph node status, histologic grade, ER status, PR status, HER2 status, p53 mutation). Body mass index (BMI) was calculated and a value of ${\geq}30$ was considered as indicative of obesity. Results: 14.9% (n=132) of the patients had TNBC. There was no difference among the patients in terms of median age, comorbid conditions and menopausal status. The proportion of medullary, tubular and mucinous carcinomas was significantly higher (15.9%) in the triple-negative (TN) group, while invasive lobular histology was more frequent (8.2%) among non-triple negative (NTN) cases (p<0.001). Grade 3 (G3) tumors were more frequent in the triple-negative group (p<0.001). The rate of p53 mutation was 44.3% in TN tumors versus 28.2% in the NTN group (p<0.001). The two groups were similar in terms of LN metastasis. In the NTN group, the rate of patients with BMI ${\geq}30$ was 53% among postmenopausal patients, while it was 36% among premenopausal women, and the difference was statistically significant (p<0.001). No significant difference was observed in terms of BMI between postmenopausal and premenopausal patients in the TN group (p=0.08). Conclusions: TNBC rates and clinicopathologic characteristics of the Turkish patient population were consistent with the data from Europe and America. However, no relationship between obesity and TNBC was observed in our study. The association between TNBC and obesity needs to be evaluated in a larger patient population.

• Asian Pacific Journal of Cancer Prevention
• /
• v.17 no.6
• /
• pp.2995-2999
• /
• 2016

Background: Triple-negative breast cancer (TNBC) often presents as an interval cancer with short survival upon metastasis and thus represents an important clinical challenge. The present study investigated the clinicopathologic characteristics and long term survival outcome of early and locally advanced TNBC. Materials and Methods: Medical records were reviewed retrospectively for 148 consecutive confirmed cases of TNBC treated in a single unit at our centre. Demographic profile, tumor type, histopathology details, treatment and follow-up information was recorded and immunohistochemistry was performed. Results: Age group >50 years was associated with tumors of clinical stage 3 (53.8%), pathological stage 3 (46.2%), pathological grade 3 (45.7%), presence of extracapsular extension (ECE, 48.5%) and lymphovascular invasion (LVI, 64.9%). Locally advanced breast cancers (LABCs) were characterized by pathological stage 3 (96.2%), presence of ECE (100%) and absence of LVI (46.7%) as compared to early breast cancers (EBCs) which had higher incidence of lower stage tumors (100%), absence of ECE (82%) and presence of LVI (91.9%; p-value <0.001. Better relapse free survival was observed in patients with no axillary involvement (69%; p-value <0.001) and absence of ECE (64%; p-value <0.001). Improved overall survival was seen in patients with EBC (90%; p-value 0.008), clear axilla (86%; p-value <0.001), absence of ECE (87%; p-value <0.001) and negative lymph nodes (90%; p-value 0.006). Conclusions: TNBCs are aggressive tumors which show poor long term survival. Patients with TNBC benefit from chemotherapy, thus better and less toxic treatment options are needed. Identification of newer targets and development of targeted therapies are the need of the hour.

• Asian Pacific Journal of Cancer Prevention
• /
• v.13 no.6
• /
• pp.2735-2738
• /
• 2012

Background: Our objective was to clarify the clinical and biological characteristics of basal-like breast cancer (BLBC) and non-basal-like breast cancer (TN3BKE) in Heilongjiang. Methods: We examined, by immunohistochemistry, expression of biological markers cytokeratin (CK) 5/6 and epidermal growth factor receptor (EGFR) and B cell specific moloney murine leukemia virus integration site 1( Bmi-1) in triple-negative breast cancer (TNBC). We studied the correlation between BLBC and several factors related to tumor progression, along with its prognostic value. Results: In the 229 cases of operable TNBC, BLBC was detected in 178 (77.7%) and TN3BKE- in 51 (22.2%). There was no significant difference in clinicopathological factors between them, However, BLBC was significantly associated with Bmi-1 expression (P=0.000) and shorter disease-free survival (DFS) (P = 0.045) and overall survival (OS) (P = 0.041). Conclusions: Compared with the non-basal group, patients with BLBC have a high expression of Bmi-1 and a poor prognosis.

• Biomolecules & Therapeutics
• /
• v.30 no.6
• /
• pp.585-592
• /
• 2022

Treatment of triple-negative breast cancer (TNBC) has been limited due to the lack of molecular targets. In this study, we evaluated the cytotoxicity of hydroxyzine, a histamine H1 receptor antagonist in human triple-negative breast cancer BT-20 and HCC-70 cells. Hydroxyzine inhibited the growth of cells in dose- and time-dependent manners. The annexin V/propidium iodide double staining assay showed that hydroxyzine induced apoptosis. The hydroxyzine-induced apoptosis was accompanied down-regulation of cyclins and CDKs, as well as the generation of reactive oxygen species (ROS) without cell cycle arrest. The effect of hydroxyzine on the induction of ROS and apoptosis on TNBC cells was prevented by pre-treatment with ROS scavengers, N-acetyl cysteine or Mito-TEMPO, a mitochondria-targeted antioxidant, indicating that an increase in the generation of ROS mediated the apoptosis induced by hydroxyzine. Western blot analysis showed that hydroxyzine-induced apoptosis was through down-regulation of the phosphorylation of JAK2 and STAT3 by hydroxyzine treatment. In addition, hydroxyzine induced the phosphorylation of JNK and p38 MAPK. Our results indicate that hydroxyzine induced apoptosis via mitochondrial superoxide generation and the suppression of JAK2/STAT3 signaling.

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

• Journal of Breast Cancer
• /
• v.21 no.4
• /
• pp.406-414
• /
• 2018

Purpose: T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is an emerging immune response molecule related to T-cell anergy. There has been tremendous interest in breast cancer targeting immune checkpoint molecules, especially in the triple-negative breast cancer (TNBC). This study was designed to investigate TIM-3 expression on tumor infiltrating lymphocytes (TILs), its relationships with clinicopathological parameters and expression of programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1), and its prognostic role. Methods: Immunohistochemistry on tissue microarray blocks produced from 109 samples of invasive ductal carcinoma type TNBC was performed with antibodies toward TIM-3, PD-1, PD-L1 and breast cancer-related molecular markers. Associations between their expression and clinicopathological parameters as well as survival analyses were performed. Results: TIM-3 was expressed in TILs from all 109 TNBCs, consisting of 17 cases (<5%), 31 cases (6%-25%), 48 cases (26%-50%), and 13 cases (>51%). High TIM-3 was significantly correlated with younger patients (p=0.0101), high TILs (p=0.0029), high tumor stage (p=0.0018), high PD-1 (p=0.0001) and high PD-L1 (p=0.0019), and tended to be associated with higher histologic grade, absence of extensive in situ components and microcalcification. High TIM-3 expression was significantly associated with a combinational immunophenotype group of high PD-L1 and high PD-1 (p<0.0001). High TIM-3 demonstrated a significantly better disease-free survival (DFS) (p<0.0001) and longer overall survival (OS) (p=0.0001), together with high TILs and high PD-1. In univariate survival analysis, high TIM-3 showed reduced relapse risk (p<0.0001) and longer OS (p=0.0003), together with high PD-1 expression. In multivariate analysis, high TIM-3 was statistically significant in predicting prognosis, showing better DFS (hazard ratio [HR], 0.0994; 95% confidence interval [CI], 0.0296-0.3337; p=0.0002) and longer OS (HR, 0.1109; 95% CI, 0.0314-0.3912; p=0.0006). Conclusion: In this study, we demonstrate that TIM-3 expression is an independent positive prognostic factor in TNBC, despite its association with poor clinical and pathologic features.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.5
• /
• pp.3223-3228
• /
• 2013

Gene expression profiling (GEP) has identified several molecular subtypes of breast cancer, with different clinico-pathologic features and exhibiting different responses to chemotherapy. However, GEP is expensive and not available in the developing countries where the majority of patients present at advanced stage. The St Gallen Consensus in 2011 proposed use of a simplified, four immunohistochemical (IHC) biomarker panel (ER, PR, HER2, Ki67/Tumor Grade) for molecular classification. The present study was conducted in 75 newly diagnosed patients of breast cancer with large (>5cm) tumors to evaluate the association of IHC surrogate molecular subtype with the clinical response to presurgical chemotherapy, evaluated by the WHO criteria, 3 weeks after the third cycle of 5 flourouracil, adriamycin, cyclophosphamide (FAC regimen). The subtypes of luminal, basal-like and HER2 enriched were found to account for 36.0 % (27/75), 34.7 % (26/75) and 29.3% (22/75) of patients respectively. Ten were luminal A and 14 luminal B (8 HER2 negative and 6HER2 positive). The triple negative breast cancer (TNBC) was most sensitive to chemotherapy with 19% achieving clinical-complete-response (cCR) followed by HER2 enriched (2/22 (9%) cCR), luminal B (1/6 (7%) cCR) and luminal A (0/10 (0%) cCR). Heterogeneity was observed within each subgroup, being most marked in the TNBC although the most responding tumors, 8% developing clinical-progressive-disease. The study supports association of molecular subtypes with response to chemotherapy in patients with advanced breast cancer and the existence of further heterogeneity within subtypes.

• Asian Pacific Journal of Cancer Prevention
• /
• v.17 no.7
• /
• pp.3321-3324
• /
• 2016

Background: Androgen receptors (ARs) are expressed in more than 70% of breast cancers (BCs) and have been implicated in BC pathogenesis. Some triple negative (TN)BC tumors express AR and may benefit from AR-targeted therapies. The aim of this study was to evaluate survival and the prevalence of AR expression and its correlation with other risk factors in triple negative BCs in women from Western Iran. Materials and Methods: In a retrospective study between 2009-2015, 41 patients with TNBC were referred to the Private Clinic of Oncology, Kermanshah city, Iran. ER, PR and AR-positive expression was defined as ${\geq}10%$ nuclear staining and also HER2 (2+), FISH was performed. Nuclear staining was considered representative for Ki67 and P53. The mean follow-up for the patients was 25 months. In this time, 5 patients died and 4 lost to follow-up were censored from survival analysis. Results: The mean age at diagnosis was 46.9 years (range, 24-71 years) and all patients were female. The OS rates for AR-positive and AR-negative patients were 90% and 85.1%, respectively, and the mean OS was 26.3 and 23.2 months. Therefore, there was no significant difference between the two groups (Hazard ratio: 0.580, 95% CI: 0.086-3.893, P=0.575). Conclusions: In TNBC patients, evaluation of AR status may provide additional information on prognosis and treatment. The results of studies showed that the prevalence AR expression may differ in the world and probably ethnicity can be an influencing factor.

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