Hoiseon Jeong

Epithelial-mesenchymal transition in breast cancer correlates with high histological grade and triple-negative phenotype.

Jeong H, Ryu Y‐j, An J, Lee Y & Kim A

Tumor-infiltrating lymphocytes, tumor characteristics, and recurrence in patients with early breast cancer.

Background:The balance in the immune system between immune surveillance against non–self-antigens and tolerance of self-antigens is known to be associated with the prognosis of breast cancer patients. However, immunologic signals in tumor microenvironment according to biological characteristics of cancer cells have not been clearly elucidated. CD4+ T cells, CD8+ T cells, and forkhead box P3-positive (Foxp3+) regulatory T cells (Tregs) are the main keys for immune surveillance and tolerance, respectively. We evaluated the correlations between the immunologic balance and tumor characteristics and their impact on recurrence. Patients and Methods:CD8+ T cells and Foxp3+ Tregs were detected by immunohistochemistry using the paraffin-embedded tumor samples from the 72 patients with early stage (I to III) breast cancer. Clinicopathologic data including tumor size and grade, lymph node metastasis, stage, patient’s age, expression status of estrogen receptor (ER), progesterone receptor, p53, Ki-67, and human epidermal growth factor receptor-2/neu, and recurrence were reviewed. Results:The decreased number of CD8+ T cells was significantly associated with tumors with lymph node metastasis (P=0.027), higher stage (stage III, P=0.013), and immunopositivity of Ki-67 (P=0.026). In contrast, the increased number of Foxp3+ Tregs was significantly correlated with tumors with lymph node metastasis (P=0.027), immunopositivity for p53 (P=0.026), and positive for Ki-67 (P<0.001). There were significant correlations between the increased Foxp3+ Treg/CD4+ T-cell ratio and lymph node metastasis (P=0.011), the expression of ER (P=0.023), and immunopositivity of p53 (P=0.031) and Ki-67 (P= 0.003). Of note, lower Foxp3+ Treg/CD4+ T-cell ratio was significantly associated with triple-negative breast cancer (P=0.004). Disease-free survival of analyzed patients was significantly associated with the number of Foxp3+ Tregs (dichotomized by a cutoff point of 17, P= 0.014) only. Univariate analysis indicated that tumor grade (P=0.017), the expression of ER (P=0.032), and non–triple-negative breast cancer (P=0.022) were independent prognostic factors for disease-free survival. Conclusions:Our data showed that lymph node metastases, immunopositivity of p53 and Ki67, and non–triple-negative tumors were associated with high regulatory T-cell infiltration. The role of immunologic balance as a prognostic marker for recurrence must be evaluated more clearly in the future study.

HRG-β1-driven ErbB3 signaling induces epithelial-mesenchymal transition in breast cancer cells

BackgroundHeregulin (HRG; also known as neuregulin) is a ligand for ErbB3. One of its isotypes, HRG-β1, binds to ErbB3 and forms heterodimers with other ErbB family members, thereby enhancing the proliferation and tumorigenesis of breast cancer cells. HRG stimulation may contribute to the progression of epithelial–mesenchymal transition (EMT) and tumor metastasis in breast cancer. Majority of studies regarding EMT has been concentrated on TGF-β signaling. Therefore, we investigated whether the HRG-β1 and ErbB3 activate Smad2 signaling during process of EMT in breast cancer cells.MethodsThe SK-BR-3 and MCF7 breast cancer cell lines were used. The expressions of phospho-Smad2 and EMT markers were observed by western blotting and immunofluorescence assays after treatment with HRG-β1. The cell motility and invasiveness were determined by wound healing and matrigel invasion assays. Smad2 and ErbB3 small interfering RNA (siRNA) transfections were performed to assess the involvement of ErbB3 and Smad2 in HRG-β1-induced EMT.ResultsHRG-β1 induced EMT through activation of Smad2. The expression of E-cadherin was decreased after HRG-β1 treatment, while the expressions of Snail, vimentin, and fibronectin were increased. The HRG-β1-induced expressions of Snail, vimentin, and fibronectin, and nuclear colocalization of phospho-Smad2 and Snail were inhibited by pretreatment with a PI3k inhibitor, LY294002, or two phospho-Smad2 inhibitors, PD169316 or SB203580 and cancer cell migration by HRG-β1 was inhibited. Knockdown of Smad2 by siRNA transfection suppressed the expressions of Snail and fibronectin in response to HRG-β1 stimulation and knockdown of ErbB3 suppressed the expressions of phospho-Smad2, Snail, and fibronectin induced by HRG-β1, whereas E-cadherin was increased compared with control siRNA-transfected cells. Knockdown of ErbB3 and Smad2 also decreased SK-BR-3 and MCF7 cell invasion.ConclusionsOur data suggest that HRG-β1 and ErbB3 induce EMT, cancer cell migration and invasion through the PI3k/Akt-phospho-Smad2-Snail signaling pathway in SK-BR-3 and MCF7 breast cancer cells.

Clinicopathologic significance of MYD88 L265P mutation in diffuse large B-cell lymphoma: A meta-analysis

The precise clinicopathologic significance of myeloid differentiation primary response gene (MYD88) L265P mutation in diffuse large B-cell lymphomas (DLBCLs) remains elusive. To investigate the frequency and clinicopathologic significance of the MYD88 L265P mutation in DLBCLs, we conducted a meta-analysis of 40 published studies on 2736 DLBCL patients. We collected relevant published research findings identified using the PubMed and Embase databases. The effect sizes of outcome parameters were calculated using a random-effects model. In this meta-analysis, the MYD88 L265P mutation in DLBCL showed a significant difference according to tumor sites. The overall incidence of the MYD88 L265P mutation in DLBCLs, excluding the central nervous system and testicular DLBCLs, was 16.5%. Notably, the MYD88 L265P mutation rates of CNS and testicular DLBCL patients were 60% and 77%, respectively. Interestingly, the MYD88 L265P mutation was more frequently detected in activated B-cell-like (ABC) or non-germinal center B-cell-like (GCB) than GCB subtype (OR = 3.414, p < 0.001). The MYD88 L265P mutation was significantly associated with old age and poor overall survival, but not with sex and clinical stage. This pooled analysis demonstrates that the MYD88 L265P mutation is significantly associated with the tumor sites and molecular subtypes in DLBCL patients.

Effectiveness of Silver-enhanced In Situ Hybridization for Evaluating HER2 Gene Status in Invasive Breast Carcinoma: A Comparative Study

BACKGROUND AND AIMS HER2 gene amplification occurs in breast cancers and has implications for treatment and prognosis. Recently, a new direct evaluation technique, silver enhanced in situ hybridization (SISH) was developed for evaluating HER2 gene status. This study was performed to evaluate the SISH technique for clinical use by comparing it to that of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). METHODS We studied 543 cases of excised breast specimens diagnosed as invasive ductal carcinoma by IHC, FISH, and SISH using a tissue microarray. IHC, FISH, and SISH results were interpreted according to the American Society of Clinical Oncology/College of American Pathologists guidelines. A total of seven English studies that reported the concordance rates of SISH and BDISH compared to FISH published before July 2011 were retrieved. RESULTS The consensus concordance rate between SISH and FISH was 96.69% (kappa value = 0.9175). The pooled sensitivity was 0.94 [95% confidence interval (CI) = 0.91-0.97], and the pooled specificity was 0.98 (95% CI = 0.96-099) in a meta-analysis of the retrieved studies and this study. Area under the receiver operating characteristics curve was 0.9906. CONCLUSIONS SISH technique is an effective modality and is comparable with FISH for evaluating HER2 gene amplification in patients with breast carcinoma.

Unique characteristics of ARID1A mutation and protein level in gastric and colorectal cancer: A meta-analysis

Background/Aim: Recently, AT-rich interactive domain-containing 1A protein (ARID1A) has been identified as a novel tumor suppressor gene in gastric cancer (GC) and colorectal cancer (CRC). However, the clinicopathologic value of ARID1A mutation or protein level in GC and CRC patients is controversial. Hence, we conducted a meta-analysis on the relationship between ARID1A aberrations and clinicopathologic parameters in GC and CRC. Materials and Methods: Relevant published studies were selected from PubMed and EMBASE. The effect sizes of ARID1A mutation or level on the patients clinicopathologic parameters were calculated by prevalence rate or odds ratio (OR) or hazard ratio (HR), respectively. The effect sizes were combined using a random-effects model. Results: The frequency of ARID1A mutation and loss of ARID1A protein expression in GC patients was 17% and 27%, respectively. The loss of ARID1A protein expression of GC patients was significantly associated with advanced tumor depth (OR = 1.8, P = 0.004), lymph node metastasis (OR = 1.4, P = 0.001), and unfavorable adjusted overall survival (HR = 1.5, P < 0.001). ARID1A mutation of GC was significantly associated with microsatellite instability (MSI) (OR = 24.5, P < 0.001) and EBV infection (OR = 2.6, P = 0.001). The frequency of ARID1A mutation and ARID1A protein expression loss in CRC patients was approximately 12–13%. Interestingly, the loss of ARID1A protein expression in CRC patients was significantly associated with poorly differentiated grade (OR = 4.0, P < 0.001) and advanced tumor depth (OR = 1.8, P = 0.012). Conclusion: Our meta-analysis revealed that ARID1A alterations may be involved in the carcinogenesis of GC by EBV infection and MSI. The loss of ARID1A protein expression may be a marker of poor prognosis in GC and CRC patients.

Comparison of Unsatisfactory Samples from Conventional Smear versus Liquid-Based Cytology in Uterine Cervical Cancer Screening Test.

Background Cervical cytology for uterine cervical cancer screening has transitioned from conventional smear (CS) to liquid-based cytology (LBC), which has many advantages. The aim of this study was to compare the proportion of unsatisfactory specimens from CS versus LBC at multiple institutions including general hospitals and commercial laboratories. Methods Each participating institution provided a minimum of 500 Papanicolaou (Pap) test results for analysis. Pap tests were classified according to the participating institution (commercial laboratory or general hospital) and the processing method (CS, ThinPrep, SurePath, or CellPrep). The causes of unsatisfactory results were classified as technical problems, scant cellularity, or complete obscuring factors. Results A total of 38,956 Pap test results from eight general hospitals and three commercial laboratories were analyzed. The mean unsatisfactory rate of LBC was significantly lower than that of CS (1.26% and 3.31%, p = .018). In the LBC method, samples from general hospitals had lower unsatisfactory rates than those from commercial laboratories (0.65% vs 2.89%, p = .006). The reasons for unsatisfactory results were heterogeneous in CS. On the other hand, 66.2% of unsatisfactory results in LBC were due to the scant cellularity. Conclusions Unsatisfactory rate of cervical cancer screening test results varies according to the institution and the processing method. LBC has a significantly lower unsatisfactory rate than CS.

Abstract LB-298: EGF induces EMT through PI3K/Akt and MAPK singnaling pathways in breast cancer cell lines

EMT, epithelial-mesenchymal transition, is defined by the loss of epithelial characteristics and the acquisition of mesenchymal properties, such as reduced cell to cell contact, spindle morphology, expression mesenchymal markers and migratory function. In carcinogenesis, EMT is known to be associated with increased aggressiveness, and invasive and metastatic potential. Although various factor, such as EGF signaling pathways, cytokines, miRNAs, Wnt signaling and TGF-s signaling have been suggested as inducers of EMT signaling pathway, detailed mechanism haven9t been clarified except TGF-s induced EMT. This study was designed to evaluate if and how EGF can induce EMT in breast cancer cell lines. We showed EGF induced EMT, such as elongation of cancer cells, down regulation of E-cadherin, and upregulation of vimentin and fibronectin in MCF-7 and MDA-MB-231 cell lines. In addition, we confirmed that EMT by EGF was induced via MAPK and PI3K/Akt signaling pathway using LY294002 (PI3K inhibitor) and PD98059 (MAPK inhibitor). PI3K inhibitor and MAPK inhibitor also blocked phosphorylation of Smad2 and inhibited nuclear localization of p-Smad2. With using SB203580 (p-Smad2 inhibitor) inhibited expression of Snail. In summary, EGF induces EMT through PI3K/Akt and MAPK signaling pathways, which activate downstream of Smad2 and Sanil signaling in MCF-7 and MDA-MB-231 cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-298. doi:1538-7445.AM2012-LB-298