Prognosis In Invasive Breast Cancer Research Articles

RNF126 as a Biomarker of a Poor Prognosis in Invasive Breast Cancer and CHEK1 Inhibitor Efficacy in Breast Cancer Cells.

Purpose: (i) To investigate the expression of the E3 ligase, RNF126, in human invasive breast cancer and its links with breast cancer outcomes; and (ii) to test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell-cycle checkpoint kinase, CHEK1.Experimental Design: A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive breast cancer and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHEK1 expression was determined by chromatin immunoprecipitation and a CHEK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHEK1 inhibition was evaluated in cells, with or without RNF126 knockdown, by MTT/colony formation, replication stress biomarker immunostaining and DNA fiber assays.Results: RNF126 protein expression was elevated in breast cancer tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an independent predictor. RNF126 promotes CHEK1 transcript expression. Critically, a strong correlation between RNF126 and CHEK1 proteins was identified in breast cancer tissue and cell lines. The inhibition of CHEK1 induced a greater cell killing and a higher level of replication stress in breast cancer cells expressing RNF126 compared to RNF126 depleted cells.Conclusions: RNF126 protein is highly expressed in invasive breast cancer tissue. The high expression of RNF126 is an independent predictor of a poor prognosis in invasive breast cancer and is considered a potential biomarker of a cancer's responsiveness to CHEK1 inhibitors. CHEK1 inhibition targets breast cancer cells expressing higher levels of RNF126 by enhancing replication stress. Clin Cancer Res; 24(7); 1629-43. ©2018 AACR.

Mediator complex (MED) 7: a biomarker associated with good prognosis in invasive breast cancer, especially ER+ luminal subtypes

BackgroundMediator complex (MED) proteins have a key role in transcriptional regulation, some interacting with the oestrogen receptor (ER). Interrogation of the METABRIC cohort suggested that MED7 may regulate lymphovascular invasion (LVI). Thus MED7 expression was assessed in large breast cancer (BC) cohorts to determine clinicopathological significance.MethodsMED7 gene expression was investigated in the METABRIC cohort (n = 1980) and externally validated using bc-GenExMiner v4.0. Immunohistochemical expression was assessed in the Nottingham primary BC series (n = 1280). Associations with clinicopathological variables and patient outcome were evaluated.ResultsHigh MED7 mRNA and protein expression was associated with good prognostic factors: low grade, smaller tumour size, good NPI, positive hormone receptor status (p < 0.001), and negative LVI (p = 0.04) status. Higher MED7 protein expression was associated with improved BC-specific survival within the whole cohort and ER+/luminal subgroup. Pooled MED7 gene expression data in the external validation cohort confirmed association with better survival, corroborating with the protein expression. On multivariate analysis, MED7 protein was independently predictive of longer BC-specific survival in the whole cohort and Luminal A subtype (p < 0.001).ConclusionsMED7 is an important prognostic marker in BC, particularly in ER+luminal subtypes, associated with improved survival and warrants future functional analysis.

Targeting breast cancer cells with a CuInS2/ZnS quantum dot-labeled Ki-67 bioprobe.

The aim of the present study was to develop a water-soluble biomarker for the detection of breast cancer using quantum dots (QDs) conjugated to Ki-67, a nuclear protein associated with the cell cycle. Ki-67 is also a marker of cell proliferation, with expression levels categorizing good and poor prognosis in invasive breast cancer. Ki-67 is a clinically used biomarker for breast cancer diagnosis, treatment and prognosis. Owing to the optical and chemical advantages of QDs, QD-based nanotechnology may aid the construction of a biomedical imaging platform for the study of cancer cell behavior. In the present study, a biomarker was prepared by employing the water-soluble CuInS2/ZnS QDs conjugated to an anti-Ki-67 monoclonal antibody to detect Ki-67 expression in breast cancer. The QDs, which were hydrophobic and coated with octadecylamine, were encapsulated with an amphiphilic biocompatible centipede-like polymer, and then conjugated to anti-Ki-67 monoclonal antibodies (QD-Ki-67 probes). The QD-Ki-67 probes retained the original optical properties of the unadorned QDs and did not exhibit distinct toxic side effects in in vitro cytotoxicity experiments. Therefore, this CuInS2/ZnS QD-labeled bioprobe, with a high quantum yield and low cytotoxicity, is a promising candidate for bioimaging and may be used as a cell label.

Upregulation of transmembrane 4 L6 family member 1 predicts poor prognosis in invasive breast cancer: A STROBE-compliant article.

Transmembrane 4 L6 family member 1 (TM4SF1) belongs to the 4-transmembrane-domain family and functions as an oncogene in multiple human cancers. In this work, we aim to determine TM4SF1 expression and its prognostic impact on patients with invasive breast cancer.Overall, we enrolled 209 invasive breast cancer patients and immunohistochemically examined the expression of TM4SF1 in tumor specimens. The relationship between TM4SF1 expression and clinicopathological parameter and patient survival of breast cancer patients was analyzed.Among the 209 cases, 137 (65.6%) exhibited high expression of TM4SF1. High TM4SF1 expression was significantly associated with advanced histological grade and negative estrogen receptor and progesterone receptor status. Triple-negative breast cancer (TNBC) tumors were more likely to express high levels of TM4SF1 than non-TNBC cases. Patients with high tumoral expression of TM4SF1 had a significantly shorter disease-free survival (DFS; P = .00) and overall survival (OS; P = .01) than those with low expression of TM4SF1. When survival analysis was restricted to the 167 patients (79.9%) receiving adjuvant chemotherapy, TM4SF1 expression was also correlated with poorer DFS and OS (P = .00). In multiple Cox regression analysis TM4SF1 expression remained an independent prognostic indicator for OS and DFS.TM4SF1 is upregulated and serves as an independent poor prognostic indicator in invasive breast cancer.

Synergistic inhibitory effects of an engineered antibody-like molecule ATF-Fc and trastuzumab on tumor growth and invasion in a human breast cancer xenograft mouse model.

The overexpression of the oncogene human epidermal growth factor receptor 2 (HER-2) has been associated with decreased disease-free survival and is a marker of poor prognosis of invasive breast cancer. Although the high efficacy of trastuzumab, a drug that targets the HER-2 oncogene, has been widely recognized, the efficiency of the treatment remains at ~30%. Therefore, novel effective treatments are required for patients with recurrent metastatic breast cancer. The present study aimed to investigate the effects of an engineered antibody-like molecule administered alone or in combination with trastuzumab on the tumor growth and metastasis of HER-2-positive breast cancer. Another aim was to investigate novel cancer therapies for HER-2-positive breast cancer. The engineered antibody-like molecule consists of the amino-terminal fragment (ATF) of human urokinase-type plasminogen (uPA) and is conjugated with the Fc fragment of human immunoglobulin G1 (ATF-Fc). The anti-cancer effect of ATF-Fc (alone and in combination with trastuzumab) on tumor cells and in a nude mouse tumor model was evaluated by detecting the expression of uPA, urokinase plasminogen activator receptor (uPAR) and HER-2. In vitro experiments demonstrated that specifically blocking the uPA-uPAR and HER-2 signaling pathways may effectively promote the apoptosis of breast cancer cells. Additionally, ATF-Fc-induced cell death in HER-2-positive breast cancer cells was observed in vivo. When ATF-Fc was administered in combination with trastuzumab, cell death was increased and breast cancer metastasis was reduced. The novel engineered antibody-like molecule ATF-Fc was able to inhibit HER-2-positive breast cancer cell growth and metastasis by interfering with uPA and its receptor (uPA-uPAR) system. Additionally, the antibody-like molecule exhibits a synergistic inhibitory effect when administered in combination with trastuzumab.

Rho-GTPase activating-protein 18: a biomarker associated with good prognosis in invasive breast cancer

Background:The prognostic value of lymphovascular invasion (LVI) in breast cancer (BC) has been demonstrated in several independent studies. However, identification of driver molecules for LVI remains a challenging task. Large-scale transcriptomic profiling of histologically validated LVI can potentially identify genes that regulate LVI.Methods:Integrative bio-informatics analyses of the METABRIC study were performed utilising a subset of strictly defined LVI using histological and immunohistochemical (IHC) criteria. ARHGAP18 was among the top differentially expressed genes between LVI+ and LVI− BC with a 1.8-fold change. The prognostic impact of ARHGAP18 gene expression was assessed in the METABRIC data set (n=1980) and externally validated using the online BC gene expression data sets utilising bc-GenExMiner v4.0 (n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large cohort of invasive BC (n=959) with long-term follow-up using IHC.Results:Pooled analysis of ARHGAP18 mRNA expression showed that overexpression was associated with better outcome (P<0.001, hazard ratio (HR)=0.82, 95% CI 0.75–0.90). ARHGAP18 protein was expressed in the cytoplasm and nuclei of the tumour cells and its expression was positively associated with good prognostic variables. Lack of cytoplasmic expression showed associations with LVI (P=0.006), epithelial-mesenchymal transition and the HER+ subtype (P=0.01). Loss of nuclear expression was associated with higher grade, HER2+ and high Ki67LI (P=0.001). Cytoplasmic and nuclear expression showed a positive association with improved survival independent of other variables (P=0.01, HR=0.74, 95% CI 0.60–87).Conclusions:ARHGAP18 expression at transcriptomic and protein levels is associated with improved patients’ outcomes whose deregulation may play a role in tumour progression and the development of LVI in BC. Further assessment of its potential therapeutic value in BC is warranted.

RUVBL1-ITFG1 interaction is required for collective invasion in breast cancer

BackgroundThe mechanisms of breast cancer collective invasion are poorly understood limiting the metastasis therapy. The ATPase RUVBL1 is frequently overexpressed in various cancers and plays a crucial role in oncogenic process. We further investigated the role of RUVBL1 in promoting collective invasion and uncovered that targeting RUVBL1 could inhibit metastatic progression. MethodsThe expression levels of RUVBL1 and ITFG1 were examined by Western blot and qRT-PCR. Co-localization and interaction of RUVBL1 and ITFG1 were determined by immunofluorescence and co-immunoprecipitation. The invasive ability was examined by transwell assay and microfluidic assay. The metastatic and tumorigenic abilities of breast cancer cells were revealed in BALB/c nude mice by xenograft and tail vein injection. ResultsATPase RUVBL1 is highly expressed in breast cancer and predicts the poor prognosis. Elevated expression of RUVBL1 is found in high metastatic breast cancer cells. Silencing RUVBL1 suppresses cancer cell expansion and invasion in vitro and in vivo. RUVBL1 interacts with a conserved transmembrane protein ITFG1 in cytoplasm and plasma membrane to promote the collective invasion. Using a microfluidic model, we demonstrated that silencing RUVBL1 or ITFG1 individually compromises collective invasion of breast cancer cells. ConclusionRUVBL1 is a vital regulator for collective invasion. The interaction between RUVBL1 and ITFG1 is required for breast cancer cell collective invasion and progression. General significanceTargeting collective invasion promoted by RUVBL1-ITFG1 complex provides a novel therapeutic strategy to improve the prognosis of invasive breast cancer.

Correlation between expression of ARID1A with prognosis of invasive breast cancer

Correlation between expression of ARID1A with prognosis of invasive breast cancer

A Comprehensive Model for Predicting Recurrence and Survival in Cases of Chinese Postoperative Invasive Breast Cancer

We investigated relationships between clinical pathologic data, molecular biomarkers and prognosis of invasive breast cancer based on a Chinese population. Immunohistochemistry (IHC) was used to assess the status of ER, PR, HER-2 and Ki-67, with fluorescence in situ hybridization (FISH) performed to further confirm HER-2 positivity with an equivocal result (IHC 2+). Subsequently, Kaplan-Meier univariate and multivariate COX regression analyses of ER, PR, HER-2, Ki-67, clinical features, therapeutic status and follow-up data were performed according to the establishment principle of the Nottingham prognostic index (NPI). From this study, age, tumor size, lymph node status, ER, HER-2, Ki-67 status were found to be associated with prognosis. Eventually, a prognostic model of (PI= (1.5×age) - size + (0.1×lymph node status) - (0.5×ER) + (2×HER-2) - (0.2×Ki-67)) was established with 288 randomly selected patients and verified with another 100 cases with invasive breast cancer. Pearson correlation analysis demonstrated a significant positive correlation index of 0.376 (P=0.012<0.05) between the prognostic index (PI) and actual prognosis. Remarkably, the consistency with the model predicted recurrence was 93% in the validation set. Therefore, it appears feasible to predict the prognosis of individuals with invasive breast cancer and to determine optimal therapeutic strategy with this model.

Clinicopathological analysis of CD44 and CD24 expression in invasive breast cancer.

A subpopulation of breast cancer cells with cluster of differentiation (CD)44-positive and CD24-negative expression has been reported to have stem cell properties and to have a higher tumorigenic capacity than other cells. However, the clinicopathological characteristics of this subpopulation are not fully understood. In this study, we aimed to identify the correlations between the expression of CD44 and CD24 and clinicopathological parameters and overall survival. We studied specimens from 262 patients with invasive breast cancer. Immunohistochemical staining for CD44 and CD24 was performed using tissue microarrays. The clinicopathological factors were evaluated from the patients' medical records. In correlation analysis, CD44 expression was significantly associated with human epidermal growth factor receptor 2 (HER2)-negative status (P<0.001). Conversely, CD24 expression was significantly associated with HER2-positive status (P<0.001). CD44 and CD24 expression did not demonstrate any correlation with the age, tumor size, axillary lymph node metastasis status, tumor stage, histological grade, estrogen receptor status and progesterone receptor status of patients. Upon survival analysis, there was no statistical difference in overall survival according to the expression of CD44 and CD24. The results from this study suggest that CD44 and CD24 are clinically significant markers associated with breast tumorigenesis, but not sufficient factors in determining the prognosis of invasive breast cancer.

A microscopic landscape of the invasive breast cancer genome.

Histologic grade is one of the most important microscopic features used to predict the prognosis of invasive breast cancer and may serve as a marker for studying cancer driving genomic abnormalities in vivo. We analyzed whole genome sequencing data from 680 cases of TCGA invasive ductal carcinomas of the breast and correlated them to corresponding pathology information. Ten genetic abnormalities were found to be statistically associated with histologic grade, including three most prevalent cancer driver events, TP53 and PIK3CA mutations and MYC amplification. A distinct genetic interaction among these genomic abnormalities was revealed as measured by the histologic grading score. While TP53 mutation and MYC amplification were synergistic in promoting tumor progression, PIK3CA mutation was found to have alleviated the oncogenic effect of either the TP53 mutation or MYC amplification, and was associated with a significant reduction in mitotic activity in TP53 mutated and/or MYC amplified breast cancer. Furthermore, we discovered that different types of genetic abnormalities (mutation versus amplification) within the same cancer driver gene (PIK3CA or GATA3) were associated with opposite histologic changes in invasive breast cancer. In conclusion, our study suggests that histologic grade may serve as a biomarker to define cancer driving genetic events in vivo.

Effect of Lump Size and Nodal Status on Prognosis in Invasive Breast Cancer: Experience from Rural India.

Breast cancer is now the leading cause of cancer among Indian women. Usually large tumour size and axillary lymph node involvement are linked with adverse outcome and this notion forms the basis of screening programs i.e. early detection. The present study was carried out to analyse relationship between tumour size, lymph node status and there relation with outcome after treatment. Fifty patients with cytology-proven invasive breast tumours were evaluated for size, clinical and pathologic characteristics of tumour, axillary lymph node status and outcome data recorded on sequential follow-up. Mean age of all participated patients was 52.24±10 years. Most common tumour location was in the upper outer quadrant with mean size of primary tumour being 3.31±1.80cm. On pathology number of lymph nodes examined ranged from 10 to 24 and 72% of patients recorded presence of disease in axilla. Significant positive correlation (p<0.013; r(2)=0.026) between tumour size and axillary lymph node involvement on linear regression. Also an indicative correlation between size and grade of tumour and axillary lymph node status was found with survival from the disease. The present study highlights that the size of the primary tumour and the number of positive lymph nodes have an inverse linear relationship with prognosis. Despite advances in diagnostic modalities, evolution of newer markers and genetic typing both size of tumour as T and axillary lymphadenopathy as N form an integral part of TNM staging and are of paramount importance for their role in treatment decisions and illustrate prognosis in patients with invasive breast cancer.

Prognosis of invasive breast cancer after adjuvant therapy evaluated with VEGF microvessel density and microvascular imaging.

The aim of this study was to investigate the role of ultrasonographic microvascular imaging in the evaluation of prognosis of patients with invasive breast cancer treated by adjuvant therapies. A total of 121 patients with invasive breast cancer underwent ultrasonographic contrast-enhanced imaging, vascular endothelial growth factor (VEGF) staining, and microvessel density (MVD) counts. The parameters of microvascular imaging and the expression of VEGF and MVD in primary breast cancer were calculated. The correlation between these factors and the overall and progression-free survival rate were analyzed using the Kaplan-Meier method. Among 121 cases, the positive VEGF cases were 75 and negative ones were 46. The cut point of 52.3 was calculated by the regressive curve for MVD counts. The data showed the mean intensity (MI) was positively associated with both the MVD counts (r = .51, p < .001) and VEGF expression (r = .35, p < .001). For the prognosis of patients, high VEGF expression and MVD counts were associated with reduced progressive and survival times (PFS, p = .032 and p = .034; OS, p = .041 and p = .038, respectively). The correlation between parameters of microvascular imaging, VEGF expressive status, and the MVD counts were established. The cut point of mean intensity (MI = 40) was used to investigate as an independent predictor for PFS (p = .021) and OS (p = .025), respectively, due to a strong correlation between MVD counts and VEGF expression in patients with invasive breast cancer. The microvascular imaging could be a visual and helpful tool to predict the prognosis of patients with invasive breast cancer treated by adjuvant therapies.

Abstract P2-04-10: Utility of simultaneous HER2 protein and gene assessment for the evaluation of discrepancy and intratumoral heterogeneity of HER2 status and the prediction of prognosis in invasive breast cancer using the gene-protein assay (GPA)

Abstract Background: The eligibility of patients for HER2-targeted therapies is determined by the evaluation of HER2 gene amplification and HER2 protein overexpression. The gene-protein assay (GPA, Ventana Medical Systems, Inc., USA) is a new method for simultaneous evaluation of HER2 immunohistochemistry (IHC) and dual in situ hybridization (DISH) using a single tissue section. In this study, we investigated the relationship between HER2 IHC and DISH results evaluated by GPA. In addition, we analyzed the correlation between HER2 status and prognosis of invasive breast cancer patients. Patients and Methods: In this study, invasive carcinoma tissues of 280 consecutive patients treated in Saitama Cancer Center in 2000-2001 (median follow-up: 130 months) were examined. Among HER2 positive initial samplings, no patients originally received adjuvant trastuzumab therapy. However, 76% of HER2 positive cases of recurrence received trastuzumab therapy. GPA was performed on a section of routinely processed primary tumor and the status of HER gene and protein were separately evaluated in whole areas of tumor sections using the following FDA criteria: DISH (negative: HER2/CEN17 &amp;lt; 2, positive: HER2/CEN17 ≥ 2.0) and IHC (score 0 to 3+). In IHC score 2+ patients group, final HER2 positivity was decided according to DISH results using criteria of FDA criteria. Recurrence-free survival (RFS) and cancer-specific survival (CSS) stratified by IHC and DISH results were analyzed. In addition, patterns of heterogeneity were grouped according to the following 4 phenotypic and genotypic types: A) IHC 2+/DISH+; B) IHC 2+/DISH-; C) IHC 1+ &amp; 0/DISH+; and D) IHC 1+ &amp; 0/DISH-. The presence of heterogeneity in relation to prognosis was analyzed in the IHC 0 &amp; 1+/DISH- group. Results: The HER2 IHC 3+ group (27.5%), both with or without trastuzumab therapy, had significantly worse survival than HER2 IHC 1+ &amp; 0 group (RFS: P=0.0039; CSS: P=0.0362) and HER2 DISH+ group (27.5%) had significantly worse survival than HER2 DISH- group (RFS: P=0.0056; CSS: P=0.0497). HER2 positive group defined by FDA criteria had significantly worse RFS than HER2 negative group (P=0.0211). HER2 IHC 1+ &amp; 0/DISH+ group had significantly worse RFS than IHC 1+ &amp; 0/DISH- group (P=0.0208). In the HER2 IHC 1+ &amp; 0/ DISH- group, patients with heterogeneity (33 cases) had significantly worse survival than those without heterogeneity (RFS: P=0.0176; CSS: P=0.0199). Conclusions: HER2 GPA technology might be useful for evaluating the discrepancy and heterogeneity of HER2 IHC and DISH results at single cell levels simultaneously and the presence of HER2 tumor cell heterogeneity might be a potent prognostic factor in HER2 negative breast cancer patients. Further clinical research must be conducted for clarification of the relationship between the presence of HER2 intratumoral heterogeneity and the effectiveness of HER2-targeted therapies. Citation Format: Sasagu Kurozumi, Mary Padilla, Masafumi Kurosumi, Hiroshi Matsumoto, Yuji Hayashi, Katsunori Tozuka, Shigenori E Nagai, Kenichi Inoue, Hanako Oba, Jun Horiguchi, Izumi Takeyoshi, Jim Ranger-Moore, Eslie Dennis, Hiroaki Nitta. Utility of simultaneous HER2 protein and gene assessment for the evaluation of discrepancy and intratumoral heterogeneity of HER2 status and the prediction of prognosis in invasive breast cancer using the gene-protein assay (GPA) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-04-10.

Acid ceramidase is associated with an improved prognosis in both DCIS and invasive breast cancer

Acid ceramidase (ASAH1) a key enzyme of sphingolipid metabolism converting pro-apoptotic ceramide to sphingosine has been shown to be overexpressed in various cancers. We previously demonstrated higher expression of ASAH1 in ER positive compared to ER negative breast cancer. In the current study we performed subtype specific analyses of ASAH1 gene expression in invasive and non invasive breast cancer. We show that expression of ASAH1 is mainly associated with luminal A – like cancers which are known to have the best prognosis of all breast cancer subtypes. Moreover tumors with high ASAH1 expression among the other subtypes are also characterized by an improved prognosis. The good prognosis of tumors with high ASAH1 is independent of the type of adjuvant treatment in breast cancer and is also detected in non small cell lung cancer patients. Moreover, even in pre-invasive DCIS of the breast ASAH1 is associated with a luminal phenotype and a reduced frequency of recurrences. Thus, high ASAH1 expression is generally associated with an improved prognosis in invasive breast cancer independent of adjuvant treatment and could also be valuable as prognostic factor for pre-invasive DCIS.

MiR-320a is an independent prognostic biomarker for invasive breast cancer.

Breast cancer is one of the most common malignancies worldwide and is the second leading cause of cancer-related mortality among females. miRNAs are a class of small noncoding RNAs that are aberrantly expressed in human cancers. Due to their small size and stability, miRNAs have the potential to be efficacious clinical targets. MicroRNA-320a (miR-320a) has been shown to be dysregulated in multiple malignancies. In the present study, the expression levels of miR-320a were investigated in 15 paraffin-embedded in situ breast carcinoma and 130 invasive breast cancer tissues, and the prognostic value for breast cancer patients was assessed. Chromogenic in situ hybridization revealed that 60/130 (46%) invasive breast cancer tissues exhibited high expression levels of miR-320a (staining index score of ≥4). Furthermore, miR-320a staining was found to significantly correlate with tumor size (P=0.046), clinical stage (P<0.001), lymph node metastasis (P<0.001) and distant metastasis (P=0.006). In addition, patients exhibiting low miR-320a expression levels had shorter overall survival times (P<0.001). Univariate and multivariate analyses revealed that miR-320a was an independent prognostic biomarker for invasive breast cancer (hazard ratio, 0.221; 95% confidence interval, 0.050–0.979; P=0.047). Receiver operator characteristic curves revealed that the prognostic value of miR-320a was enhanced when compared with the widely used prognostic biomarkers (estrogen receptor, progesterone receptor and human epidermal growth factor-2) in invasive breast cancer. The results of the present study suggest that miR-320a presents a potential biomarker for the prognosis of invasive breast cancer, and dysregulation of miR-320a may be involved in invasive breast cancer progression.

Anti-HER2 CD4 T helper type 1 response in breast cancer: Is there a role for immunorestoration?

636 Background: Tumor microenvironment infiltration of IFNγ-producing CD4 T helper 1 (Th1) cells is linked to improved prognosis in invasive breast cancer (IBC). We investigated circulating anti-HE...

CD10-a new prognostic stromal marker in breast carcinoma, its utility, limitations and role in breast cancer pathogenesis.

Breast cancer is one of the leading causes of mortality in Indian women. Although breast cancer is an epithelial malignancy, stroma plays a key role in its development and pathogenesis. Stromal markers are now emerging as novel markers in assessing the prognosis of invasive breast cancer and have not been studied extensively till date. The aim of the present study is to study the stromal expression of CD10 in breast carcinoma, find its relationship with other prognostic markers and study the role stroma plays in breast cancer pathogenesis. A total of 70 cases of breast cancer were included in the study. Representative sections were taken and hematoxylin and eosin staining was done. Immunohistochemistry was performed with ER, PR, Her2neu and CD10. Stromal expression of CD10 (>10% stromal positivity was considered positive) in invasive breast carcinoma was noted and was statistically analyzed with different known prognostic markers of breast carcinoma. Stromal expression of CD10 was found to be significantly associated with increasing tumor grade (P = 0.04), increasing mitotic rate (P = 0.33), worsening prognosis (P = 0.01), ER negativity (P = 0.0001), Her2neu positivity (P = 0.19) and with molecular subtypes (CD10 positivity with the HER2 type, and CD10 negativity with Luminal type). No correlation was found between CD10 overexpression and PR, age, menopausal status, tumor size, lymph node positivity and tumor stage. This study gives substantial proof to the various models/research papers explaining the role of stroma/CD10 in breast cancer pathogenesis. Keeping the role stroma plays in predicting prognosis and tumor response, CD10 should be included as a routine pre-chemotherapy marker in breast carcinoma. Further studies should be performed to see the role stroma plays in hormonal expression and the usefulness of CD10 to predict treatment failure in breast carcinomas receiving neoadjuvant therapy.

β-elemene decreases cell invasion by upregulating E-cadherin expression in MCF-7 human breast cancer cells

Inactivation of E-cadherin results in cell migration and invasion, hence leading to cancer aggressiveness and metastasis. Downregulation of E-cadherin is closely correlated with a poor prognosis in invasive breast cancer. Thus, re-introducing E-cadherin is a novel strategy for cancer therapy. The aim of the present study was to determine the effects of the traditional Chinese medicine, β-elemene (ELE), on E-cadherin expression, cell migration and invasion in the breast cancer cell line MCF-7. MCF-7 cells were treated with 50 and 100µg/ml ELE. E-cadherin mRNA was analyzed by reverse transcription‑polymerase chain reaction. E-cadherin protein levels were determined by immunofluorescence and western blot assays. Cell motility was measured by a Transwell assay. ELE increased both the protein and mRNA levels of E-cadherin, accompanied by decreased cell migration and invasion. Further analysis demonstrated that ELE upregulated estrogen receptor‑α (ERα) and metastasis-associated protein3 (MTA3), and decreased the nuclear transcription factor Snail. In conclusion, our results demonstrate that ELE decreases cell migration and invasion by upregulating E-cadherin expression via controlling the ERα/MTA3/Snail signaling pathway.

Expression of autophagy‐related markers beclin‐1, light chain 3A, light chain 3B and p62 according to the molecular subtype of breast cancer

To investigate the relationship between the expression of autophagy-related proteins, including beclin-1, light chain (LC) 3A, LC3B, and p62, and prognosis in invasive breast cancer. We constructed tissue microarrays from the breast cancer cells of 489 patients, and classified molecular subtypes using surrogate immunohistochemical stains. The tumoral expression levels of LC3A and LC3B were highest in triple-negative breast cancer (TNBC) (P < 0.001), whereas these types of tumour had the lowest expression levels of these markers in the stroma (P = 0.005 and P < 0.001, respectively). Cytoplasmic beclin-1 expression was highest in TNBC, but nuclear expression was lowest (P < 0.001). p62 cytoplasmic and nuclear expression were highest in HER2-type tumours (P = 0.001 and P < 0.001, respectively). Tumoral LC3A and LC3B expression were associated with high histological grade (P < 0.001, and P < 0.028, respectively), but nuclear p62 expression was associated with lower histological grade (P = 0.004). Autophagy-related markers are differentially expressed according to the molecular subtype of breast cancer. In particular, expression of LC3A, LC3B and beclin-1 was highest in TNBC tumour cells, whereas that of LC3A and LC3B in the tumour stroma was lowest in TNBC.