Invasive Breast Carcinoma Patients Research Articles

44P Prognostic value of androgen receptor expression in premenopausal women with estrogen receptor-positive breast cancer

The prognosis of breast cancer in pre-menopausal women is very variable and dependent on the interactions of several biological factors. The androgen receptor (AR) could be among the prognostic variables related to survival although the data is scarce. The aim of the study was to examine the relationship between androgen receptor expression and survival outcomes in estrogen receptor (ER)-positive pre-menopausal invasive breast carcinoma patients.

Lidocaine promotes apoptosis in breast cancer cells by affecting VDAC1 expression

ObjectiveTo investigate the effect of lidocaine on the expression of voltage-dependent anion channel 1 (VDAC1) in breast invasive carcinoma (BRCA) and its impact on the apoptosis of breast cancer cells.MethodsWe collected clinical data from patients with invasive breast cancer from 2010 to 2020 in the First affiliated hospital of Nanchang University, evaluated the prognostic value of VDAC1 gene expression in breast cancer, and detected the expression of VDAC1 protein in breast cancer tissues and paracancerous tissues by immunohistochemical staining of paraffin sections. Also, we cultured breast cancer cells (MCF-7) to observe the effect of lidocaine on the apoptosis of MCF-7 cells.ResultsAnalysis of clinical data and gene expression data of BRCA patients showed VDAC1 was a differentially expressed gene in BRCA, VDAC1 may be of great significance for the diagnosis and prognosis of BRCA patients. Administration of lidocaine 3 mM significantly decreased VDAC1 expression, the expression of protein Bcl-2 was significantly decreased (p < 0.05), and the expression of p53 increased significantly (p < 0.05). Lidocaine inhibited the proliferation of MCF-7 breast cancer cells, increased the percentage of G2 / M phase cells and apoptosis.ConclusionLidocaine may inhibit the activity of breast cancer cells by inhibiting the expression of VDAC1, increasing the apoptosis in breast cancer cells.

Differences of Clinicopathological Features between Metaplastic Breast Carcinoma and Nonspecific Invasive Breast Carcinoma and Prognostic Profile of Metaplastic Breast Carcinoma.

Introduction Metaplastic breast carcinoma is a rare special type of breast cancer, which has distinguished clinical characteristics. We aimed to evaluate the clinicopathological features of metaplastic breast carcinoma compared with nonspecific invasive breast carcinoma and study the prognosis of metaplastic breast carcinoma. Methods We reviewed metaplastic breast carcinoma cases (n = 37) from January 2000 to December 2021 and nonspecific invasive breast carcinoma cases (n = 433) from January 2019 to December 2020 extracted from our institution retrospectively. The following variables were recorded, including the patients' general information, complications, T stage, expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67, molecular subtyping, lymph node status, skin or chest wall involvement, vessel carcinoma embolus, therapy modality (surgical treatments, chemotherapy, and radiotherapy), and survival. Results Patients with metaplastic breast carcinoma had more advanced disease than patients with nonspecific invasive breast carcinoma (T stage: P=0.0011). A greater proportion of metaplastic breast carcinoma presented with triple-negative breast cancer than nonspecific invasive breast carcinoma (79.41% vs. 12.47%, P ≤ 0.001). Our study showed that the skin or chest wall invasion was more frequent in metaplastic breast carcinoma patients (11.76% vs. 1.62%, P=0.005). The 5-year survival rate for metaplastic breast carcinoma patients was 57.66% (95% CI: 0.3195∼0.7667). No local recurrence was observed while distant metastasis occurred in 33.33% of patients with metaplastic breast carcinoma. Death due to disease occurred in 24.24% of patients with metaplastic breast carcinoma. Conclusion The majority of metaplastic breast carcinoma patients had more advanced disease and triple-negative disease than nonspecific invasive breast carcinoma patients. Also, metaplastic breast carcinoma patients had frequent skin or chest wall invasion and a high rate of distant metastasis and mortality.

Tumor budding and fibrotic focus—proposed grading system for tumor budding in invasive carcinoma no special type of the breast

Tumor budding grade is a very useful histological prognostic indicator for colorectal cancer patients. Recently, it has been also reported as a significant prognostic indicator in invasive breast carcinoma patients. Our group and others have previously reported that the presence of a fibrotic focus in the tumor is a very useful histological finding for accurately predicting the prognosis in patients with invasive carcinoma of no special type (ICNST) of the breast. The purpose of the present study was to investigate whether a grading system incorporating tumor budding in a fibrotic focus is superior to the conventional grading system for tumor budding to accurately predict outcomes in patients with ICNST. According to our new grading system, we classified the tumors into grade I (164 cases), grade II (581 cases), and grade III (110 cases), and the results clearly demonstrated the significant superiority of the new grading system over that of conventional tumor budding alone for accurately predicting outcomes in patients with ICNST. Our findings strongly suggest that tumor cells and tumor-stromal cells interaction play very important roles in tumor progression rather than tumor cells alone.

A hierarchical approach to combine histological grade and immunohistochemical factors to identify high-risk luminal breast cancers.

BackgroundThe luminal subtype accounts for ~70% of newly diagnosed breast cancer patients. Although it has a better prognosis, approximately 30% of them develop a late relapse. Identifying those patients is of interest to improve treatment decisions.MethodsA retrospective observational, single-centre study based on data from medical records of 572 non-metastatic (I–III) invasive ductal breast carcinoma patients, 448 with luminal tumours and 124 with triple-negative tumours. Kaplan–Meier, Cox regression and time-dependent Cox regression were carried out to obtain the prognosis value of risk factors.ResultsDuring a median observation of 5.5 years, 105 distant metastasis events and 105 all-cause deaths were observed. In addition to known clinicopathological factors (i.e., age, tumour size and lymph node metastasis), the high semi-quantitative expression of both hormone receptors was associated with distant metastasis-free survival (DMFS) (adjusted hazard ratio (HaR): 0.524 (0.316–0.867), p = 0.012) and overall survival (OS) (adjusted HaR: 0.486 (0.286–0.827), p = 0.008). The stratified analysis made it possible to identify risk modification factors. Subsequent stratification by histological grade, Ki-67 and semi-quantitative PR expression or, mainly, the composite semi-quantitative expression of hormone receptors (cHR) enabled the identification of luminal breast cancer patients of adjuvant schema at higher risk for metastasis and death. However, initial analyses including patients of neoadjuvant therapy pointed to a path of subsequent stratification by cHR and histological grade, also enabling grouping of luminal breast cancer patients with similar prognosis for DMFS (cHR ≤ 4+ G2 or G3 versus triple-negative, adjusted HaR: 0.703 (0.415–1.189), p = 0.189) and OS (cHR ≤4+ G2 or G3 versus triple-negative, adjusted HaR: 0.662 (0.403–1.088), p = 0.104).ConclusionThe semi-quantitative expression of both cHR, Ki-67 proliferation index and histological grade can identify luminal breast cancer patients at greater risk of developing metastasis and death when combined in a hierarchical fashion, and could be useful for a better prognosis stratification in services from low- and middle-income countries.

A combination of transcriptome and methylation analyses reveals the role of lncRNA HOTAIRM1 in the proliferation and metastasis of breast cancer.

DNA methylation status is strongly associated with the prognosis of breast invasive carcinoma (BRCA). Elucidating the mechanisms underlying DNA methylation coupled with determining its biological function is imperative to the effective development of treatment and prevention strategies for breast cancer. We retrieved transcriptome and DNA methylation profiles of BRCA patients from The Cancer Genome Atlas (TCGA) database, then applied the "limma" package in R software to identify differentially expressed genes (DEGs) and aberrantly methylated genes. Next, we used the "MethylMix" package to screen for methylation-driven genes, and performed univariate and multivariate Cox regression analyses to determine the prognostic value of the methylation-driven genes and clinical characteristics. We validated these findings in 51 breast cancer tissues alongside 51 corresponding normal tissues. Furthermore, we used cell experiments to clarify the biological function and underlying molecular mechanisms of HOTAIRM1 in vitro. A total of 25 methylation-driven genes were identified in the dataset. Results from univariate and multivariate Cox regression showed that SYN2, HOTAIRM1, BCAS1, and ALDOC were significantly associated with patient prognosis. Immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) results showed that the expression levels of SYN2 and HOTAIRM1 were negatively correlated with BRCA stage, whereas those of BCAS1 and ALDOC were positively correlated with BRCA stage. Results from in vitro experiments showed that knockdown HOTAIRM1 expression promoted breast cancer cells proliferation, clone formation, and invasion. Up-regulation of HOTAIRM1 inhibited breast cancer cells proliferation, clone formation, and invasion. In summary, low HOTAIRM1 expression is a significant prognostic factor for the survival of BRCA patients and thus could be a potential therapeutic target for the treatment of BRCA.

SET8 Inhibition Potentiates Radiotherapy by Suppressing DNA Damage Repair in Carcinomas

ObjectiveSET8 is a member of the SET domain-containing family and the only known lysine methyltransferase (KMT) that monomethylates lysine 20 of histone H4 (H4K20me1). SET8 has been implicated in many essential cellular processes, including cell cycle regulation, DNA replication, DNA damage response, and carcinogenesis. There is no conclusive evidence, however, regarding the effect of SET8 on radiotherapy. In the current study we determined the efficacy of SET8 inhibition on radiotherapy of tumors and the underlying mechanism. MethodsFirst, we explored the radiotherapy benefit of the SET8 expression signature by analyzing clinical data. Then, we measured a series of biological endpoints, including the xenograft tumor growth in mice and apoptosis, frequency of micronuclei, and foci of 53BP1 and γ-H2AX in cells to detect the SET8 effects on radiosensitivity. RNA sequencing and subsequent experiments were exploited to verify the mechanism underlying the SET8 effects on radiotherapy. ResultsLow expression of SET8 predicted a better benefit to radiotherapy in lung adenocarcinoma (LUAD) and invasive breast carcinoma (BRCA) patients. Furthermore, genetic deletion of SET8 significantly enhanced radiation treatment efficacy in a murine tumor model, and A549 and MCF7 cells; SET8 overexpression decreased the radiosensitivity. SET8 inhibition induced more apoptosis, the frequency of micronuclei, and blocked the kinetics process of DNA damage repair as 53BP1 and γ-H2AX foci remained in cells. Moreover, RNF8 was positively correlated with the SET8 impact on DNA damage repair. ConclusionOur results demonstrated that SET8 inhibition enhanced radiosensitivity by suppressing DNA damage repair, thus suggesting that SET8 potentiated radiotherapy of carcinomas. As new inhibitors of SET8 are synthesized and tested in preclinical and clinical settings, combining SET8 inhibitors with radiation warrants consideration for precise radiotherapy.

The correlation between beta-catenin expression pattern and adverse prognostic factors in a cohort of invasive breast carcinoma patients in Sri Lanka

Journal of Diagnostic Pathology is a peer reviewed journal published biannually by the College of Pathologists of Sri Lanka. The journal publishes manuscripts dealing with all aspects of pathology. The aim of the journal is to update knowledge and encourage original research in the field of pathology.

Discoidin Domain Receptor 2 Expression as Worse Prognostic Marker in Invasive Breast Cancer.

Discoidin domain receptor 2 (DDR2) is arising as a promising therapeutic target in breast carcinoma (BC). The ability of DDR2 to bind to collagen promotes protumoral responses in cancer cells that influence the tumor microenvironment (TME). Nonetheless, the interrelation between DDR2 expression and TME modulation during BC progression remains poorly known. For this reason, we aim to evaluate the correlation between intratumoral expression of DDR2 and the infiltration of the main TME cell populations, cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs). First, collagen and DDR2 expression levels were analyzed in human invasive BC samples. Then, DDR2 status correlation with tumor aggressiveness and patient survival were retrieved from different databases. Subsequently, the main pathways, cell types, and tissues correlated with DDR2 expression in BC were obtained through bioinformatics approach. Finally, we studied the association of DDR2 expression with the recruitment of CAFs and TAMs. Our findings showed that, together with the expected overexpression of TME markers, DDR2 was upregulated in tumor samples. Besides, we uncovered that altered TME markers were linked to DDR2 expression in invasive BC patients. Consequently, DDR2 modulates the stromal reaction through CAFs and TAMs infiltration and could be used as a potential worse prognostic factor in the treatment response of invasive BC.

Identification and Verification of Necroptosis-Related Gene Signature and Associated Regulatory Axis in Breast Cancer.

Background: Breast invasive carcinoma (BRCA) is the second leading cause of malignancy death among women. Necroptosis is a newly discovered mechanism of cell death involved in the progression and prognosis of cancer. The role of necroptosis-related genes (NRGs) in BRCA is still a mystery. Methods: LASSO Cox regression analysis was performed to construct a prognostic necroptosis-related signature. A ceRNA was constructed to explore the potential lncRNA-miRNA-mRNA regulatory axis in BRCA. Results: A total of 63 necroptosis-related genes were differentially expressed in BRCA. We also summarized the genetic mutation landscape of NRGs in BRCA. BRCA patients with low expression of BCL2 and LEF1, as well as high expression of PLK1 and BNIP3, had a poor OS, DSS, and DFS. A necroptosis-related prognostic signature with four genes (BCL2, LEF1, PLK1, and BNIP3) was constructed, and it could serve as a prognosis biomarker in BRCA, predicting the OS rate with medium to high accuracy. Moreover, the risk score was correlated with immune infiltration in BRCA. Further comprehensive analysis revealed that the expression of BCL2, LEF1, PLK1, and BNIP3 was correlated with tumor mutation burden, microsatellite instability, drug sensitivity, and pathology stage. Previous studies have been extensively studied. The roles of LEF1, PLK1, and BNIP3 in BRCA and BCL2 were selected for further analysis. We then constructed a ceRNA network, which identified an lncRNA LINC00665/miR-181c-5p/BCL2 regulatory axis for BRCA. Conclusion: The bioinformatics method was performed to develop a prognostic necroptosis-related prognostic signature containing four genes (BCL2, LEF1, PLK1, and BNIP3) in BRCA. We also constructed a ceRNA network and identified an lncRNA LINC00665/miR-181c-5p/BCL2 regulatory axis for BRCA. Further in vivo and in vitro studies should be conducted to verify these results.

A Three-mRNA Signature Associated with Pyrimidine Metabolism for Prognosis of BRCA.

Objective Breast invasive carcinoma (BRCA), as a systemic disease, is currently the most malignant tumor among women. Early detection of BRCA will increase the probability of cure. Pyrimidine metabolism (PyM) stands for an essential metabolic pathway related to DNA replication of cancer cells, which may also serve as a diagnostic marker and therapeutic target. Therefore, the aim of this research is to discover a prognostic signature associated with PyM for BRCA. Methods The BRCA mRNA sequencing data along with microarray data were obtained based on The Cancer Genome Atlas (TCGA) database. In addition, 4 PyM-related gene sets were profiled through gene set enrichment analysis (GSEA); it revealed the core genes differentially expressed in cancer and paracancerous tissue. Thereafter, genes were subjected to univariate as well as multivariate regression for constructing an mRNA signature to independently predict BRCA prognosis. Then, the Kaplan-Meier (KM) curve was applied for validation. The prognostic power of the signature was verified against the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) database. Results We constructed a three-mRNA (RRM2B, NME3, and POLD2) gene signature related to PyM to predict overall survival (OS) for BRCA. The as-constructed gene signature was adopted to classify cases as high- or low-risk group, identifying patients with BRCA with poor prognosis. Additionally, the risk score obtained using our constructed 3-mRNA prognosis signature is independent from other clinical variables. Conclusion Our findings suggested that PyM-related mRNA signature might be a combined prognostic biomarker for BRCA and can provide important reference that are useful for individualized treatment for BRCA patients.

STUDY OF CORRELATION OF INFLAMMATORY CELL INFILTERATION SCORE WITH TUMOR GRADE, NODAL STATUS, ER, PR, HER-2 NEU STATUS IN PATIENTS OF STAGE 2 AND 3 BREAST CANCER IN A TERTIARY CENTER, KOLKATA

Breast Cancer is the most common cancer in women in India and constitute one–third of women’s cancers and is second reason of mortality after lung carcinoma.[1] It is the most commonly diagnosed malignancy in most cities in India, and 2nd most common cancer in females in the rural areas. As the disease burden and mortality rate is very high, evaluation of several parameters that influence survival rates among women with breast cancer may help design early detection, predict the prognosis and frame a suitable line of treatment.[2] The link between inflammation and cancer was first suggested in 1863.[3] Chronic inflammation is known to increase the risk of cancer development, such as colon cancer in inflammatory bowel diseases.[4] There is good evidence that the development of cancer and its progression are dependent on a complex interaction of the tumour and the host inflammatory response.[5] Aim: This study aims to correlate the relation of inflammatory cell infilteration with tumour staging, nodal status, ER, PR, HER-2 NEU status of breast cancer. Material and Method: The proposed study was a cross sectional study with mostly prospective observation and with some retrospective observation, included 74 patients of stage II and stage III breast carcinoma who underwent MRM in Cancer Institute from 2017-2018. The various clinical and histopathological prognostic parameters along with inflammatory cell infilterate score in invasive breast carcinoma patients were studied and correlated. The inflammatory cell infilterates was assessed according to Klintrup-Makinen (K-M) criteria. It is scored on 4 point scale where score 0 defined no increase in inflammatory cell infilterate, score 1 defined as mild or patchy increase ,score 2 denoted as prominent inflammatory response with some cancer cell destruction and score 3 as florid cup like response. Further it is classified as low group score (score 0-1)and high group score (score 2-3) .[6] Result: There was significant association between inflammatory cell infiltrate score and grade of tumor (p=0.0005) (TABLE 1) .58.1% ,54.1% and 37.8% of the cases were ER, PR and Her-2/neu positive respectively. ER negative tumors (74.19%) were showing statistically significant (p= 0.01) association with high inflammatory cell infilterate score (ie. Score 2 and 3). Similarly PR negative tumors (64.7%) were showing statistically significant association (p= 0.04) with high inflammatory cell infilterate score. No such correlation was found between between HER-2 /NEU status and nodal involvement with inflammatory cell infilterate score (TABLE 3). Keywords: Breast cancer, Invasive ductal carcinoma, ER , PR , HER-2/Neu ,grade of tumor, Nodal status, inflammatory cell infilterate score.

Ultrasound for the Objective Measurement of Breast Lymphedema.

Breast lymphedema has supplanted upper extremity lymphedema as a common and debilitating sequela of breast cancer treatment, but has no objective measurement. We assessed the utility of ultrasound-measured difference in dermal thickness between affected and unaffected breasts as a measure of breast lymphedema. We associated this measure with patient characteristics, treatment parameters, and patient-reported impact on quality of life. We enrolled 30 invasive breast carcinoma patients treated with breast-conserving surgery, sentinel lymph node biopsy, and radiotherapy, and 10 control patients evaluated for benign breast conditions without prior breast surgery or radiotherapy. Patient and treatment variables were ascertained from medical records and radiotherapy instruments. Impacts on quality of life were measured with a modified Disability of the Arm, Shoulder, and Hand questionnaire. We characterized breast lymphedema by calculating the difference in ultrasound-measured dermal thickness between affected and unaffected breasts. Associations with patient characteristics, treatment, and quality of life were quantified with log-binomial regression models. Breast lymphedema was defined as a dermal thickness difference of >0.3 mm. Nineteen patients in the invasive group (63%) had breast lymphedema by this definition. We observed positive associations between ultrasound-defined breast lymphedema and surgical factors (size of primary tumor, number of lymph nodes removed), radiotherapy factors (breast volume irradiated, receipt of radiation boost), and patient-reported outcomes (sleep quality and overall confidence). Difference in dermal thickness is an easy and inexpensive measurement for quantifying breast lymphedema, and correlates with treatment parameters and patient-reported impacts on quality of life.

Potential role of BRCA1 protein expression as a prognostic tissue biomarker in breast carcinoma: an immunohistochemical and clinicopathologic study from South India

Introduction. BRCA1 dysfunction is a hallmark of both hereditary and sporadic breast cancer. BRCA1 protein expression can be lost by germline mutation, somatic mutation or promoter hypermethylation. This study aimed to explore BRCA1 dysfunction in breast cancer patients by immunohistochemistry and to study its association with prognostic factors. Material and methods. BRCA1 protein expression was assessed by immunohistochemistry on formalin fixed paraffin embedded tissue blocks of 110 invasive breast carcinoma patients. Furthermore, the clinical findings and tumor features associated with BRCA1 dysfunction were characterized. Results. Reduced BRCA1 immunoreactivity was observed in 19% of breast cancer cases. Although these patients presented with aggressive tumor characteristics, statistical significance was observed only with presence of lymphovascular emboli (p &lt; 0.05). These results suggest that loss of BRCA1 protein expression is associated with an aggressive phenotype of breast carcinoma. Conclusions. Immunohistochemistry for BRCA1 protein expression in tumor tissues may provide a less expensive screening tool to identify BRCA1 dysfunction due to genetic or epigenetic alterations.

The nomogram based on the 6-lncRNA model can promote the prognosis prediction of patients with breast invasive carcinoma

Long non-coding RNA (lncRNA) is a prognostic biomarker for many types of cancer. Here, we aimed to study the prognostic value of lncRNA in Breast Invasive Carcinoma (BRCA). We downloaded expression profiles from The Cancer Genome Atlas (TCGA) datasets. Subsequently, we screened the differentially expressed genes between normal tissues and tumor tissues. Univariate Cox, LASSO regression, and multivariate Cox regression analysis were used to construct a lncRNA prognostic model. Finally, a nomogram based on the lncRNAs model was developed, and weighted gene co-expression network analysis (WGCNA) was used to predict mRNAs related to the model, and to perform function and pathway enrichment. We constructed a 6-lncRNA prognostic model. Univariate and multivariate Cox regression analysis showed that the 6-lncRNA model could be used as an independent prognostic factor for BRCA patients. We developed a nomogram based on the lncRNAs model and age, and showed good performance in predicting the survival rates of BRCA patients. Also, functional pathway enrichment analysis showed that genes related to the model were enriched in cell cycle-related pathways. Tumor immune infiltration analysis showed that the types of immune cells and their expression levels in the high-risk group were significantly different from those in the low-risk group. In general, the 6-lncRNA prognostic model and nomogram could be used as a practical and reliable prognostic tool for invasive breast cancer.

MiR-29b-3p Increases Radiosensitivity in Stemness Cancer Cells via Modulating Oncogenes Axis.

Radioresistance conferred by cancer stem cells (CSCs) is the principal cause of the failure of cancer radiotherapy. Eradication of CSCs is a prime therapeutic target and a requirement for effective radiotherapy. Three dimensional (3D) cell-cultured model could mimic the morphology of cells in vivo and induce CSC properties. Emerging evidence suggests that microRNAs (miRNAs) play crucial roles in the regulation of radiosensitivity in cancers. In this study, we aim to investigate the effects of miRNAs on the radiosensitivity of 3D cultured stem-like cells. Using miRNA microarray analysis in 2D and 3D cell culture models, we found that the expression of miR-29b-3p was downregulated in 3D cultured A549 and MCF7 cells compared with monolayer (2D) cells. Clinic data analysis from The Cancer Genome Atlas database exhibited that miR-29b-3p high expression showed significant advantages in lung adenocarcinoma and breast invasive carcinoma patients’ prognosis. The subsequent experiments proved that miR-29b-3p overexpression decreased the radioresistance of cells in 3D culture and tumors in vivo through interfering kinetics process of DNA damage repair and inhibiting oncogenes RBL1, PIK3R1, AKT2, and Bcl-2. In addition, miR-29b-3p knockdown enhanced cancer cells invasion and migration capability. MiR-29b-3p overexpression decreased the stemness of 3D cultured cells. In conclusion, our results demonstrate that miR-29b-3p could be a sensitizer of radiation killing in CSC-like cells via inhibiting oncogenes expression. MiR-29b-3p could be a novel therapeutic candidate target for radiotherapy.

Potential Significance and Clinical Value Explorations of Calmin (CLMN) in Breast Invasive Carcinoma.

ObjectiveFunction of calmin (CLMN) was rarely reported in human diseases, especially in tumor. Present study initially assessed the significance of CLMN in breast invasive carcinoma (BRCA).MethodsExpressions of CLMN containing mRNA and protein in BRCA was firstly assessed, and association of CLMN mRNA expression with clinical phenotypes of BRCA patients was analyzed as well. Prognostic value of CLMN in BRCA was subsequently predicted based on the clinical characteristics of patients. Finally, the potential biological function associated with CLMN involved in BRCA was revealed.Results(1) The mRNA expression of CLMN was lower in BRCA compared with that in normal patients (P<0.001). However, result of CLMN total protein expression was opposite (P<0.05). (2) The mRNA expression of CLMN was statistically associated with BRCA patient’s age, gender, PR status, ER status, histological type, tumor stage, copy number, and methylation level (all P<0.05). (3) Compared with low expression group, high expression of CLMN was conducive to the overall survival of BRCA patients (P=0.0011). Detailed, survival difference between CLMN high and low expression groups was observed in patients with stage 1 (P=0.0250), positive ER status (P=0.0042), negative HER status (P=0.0433), luminal A (P=0.0065), luminal B (P=0.0123) and positive lymph node status (P=0.0069). Pathway analysis suggested that CLMN mainly participated in cell cycle process (P<0.05) and exerted inhibition effect on the cell cycle involved in BRCA (P<0.05).ConclusionCLMN mRNA high expression prolonged the survival time of patients and caused a favorable prognosis. The positive function of CLMN in BRCA required further investigation in future work.

Ceruloplasmin correlates with immune infiltration and serves as a prognostic biomarker in breast cancer.

Breast-invasive carcinoma (BRCA) is the most frequent and malignant tumor in females. Ceruloplasmin (CP) is a multifunctional molecule involved in iron metabolism, but its expression profile, prognostic potential and relationship with immune cell infiltration in BRCA are unknown. Ceruloplasmin mRNA and protein expression was significantly decreased in BRCA patients according to the Oncomine, UALCAN, GEPIA and TCGA databases. Ceruloplasmin expression was strongly correlated with various clinicopathological features of BRCA patients. BRCA patients with high ceruloplasmin expression exhibited shorter survival times than those with low ceruloplasmin expression based on the Kaplan-Meier plotter and PrognoScan databases. GO and KEGG analyses and GSEA revealed a strong correlation between ceruloplasmin and various immune-related pathways. Ceruloplasmin expression was significantly associated with the infiltration of immune cells into tumor sites by analyzing the TIMER and CIBERSORT. Additionally, ceruloplasmin was positively correlated with immune checkpoints in BRCA. These findings suggest that low ceruloplasmin expression correlates with a favorable prognosis and tumor immune cell infiltration in BRCA patients. Ceruloplasmin may serve as a therapeutic target and predict the efficacy of immunotherapy for BRCA.

Predictors of Sentinel Lymph Node Metastasis in Postoperatively Upgraded Invasive Breast Carcinoma Patients

Simple SummaryRoutine sentinel lymph node (SLN) biopsy (SLNB) is not necessary for breast-conserving surgery (BCS)-treated ductal carcinoma in situ (DCIS) but is indicated for underestimated invasive carcinoma (IC) postoperatively. In this retrospective study, we aimed to investigate the factors contributing to SLN metastasis in underestimated IC patients with an initial diagnosis of DCIS by core needle biopsy. We found that only the features related to IC, including an IC tumor size (>0.5 cm) and the presence of LVI, could be used as risk predictors of SLN metastasis. In the absence of any predictors, the incidence of positive SLNs was very low (2.6%) in the total population and extremely low (1.3%) in the BCS subgroup. Therefore, we suggest that SLNB may be omitted in patients who initially underwent BCS without risk predictors on final pathological assessment. However, further prospective studies are warranted before its clinical application.Sentinel lymph node (SLN) biopsy (SLNB) usually need not be simultaneously performed with breast-conserving surgery (BCS) for patients diagnosed with ductal carcinoma in situ (DCIS) by preoperative core needle biopsy (CNB), but must be performed once there is invasive carcinoma (IC) found postoperatively. This study aimed to investigate the factors contributing to SLN metastasis in underestimated IC patients with an initial diagnosis of DCIS by CNB. We retrospectively reviewed 1240 consecutive cases of DCIS by image-guided CNB from January 2010 to December 2017 and identified 316 underestimated IC cases with SLNB. Data on clinical characteristics, radiologic features, and final pathological findings were examined. Twenty-three patients (7.3%) had SLN metastasis. Multivariate analysis indicated that an IC tumor size > 0.5 cm (odds ratio: 3.11, p = 0.033) and the presence of lymphovascular invasion (odds ratio: 32.85, p < 0.0001) were independent risk predictors of SLN metastasis. In the absence of any predictors, the incidence of positive SLNs was very low (2.6%) in the total population and extremely low (1.3%) in the BCS subgroup. Therefore, omitting SLNB may be an acceptable option for patients who initially underwent BCS without risk predictors on final pathological assessment. Further prospective studies are necessary before clinical application.

Comprehensive analysis of suppressor of cytokine signaling proteins in human breast Cancer

BackgroundAbnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. In this study, we aimed to perform a comprehensive bioinformatic analysis of SOCS proteins in breast invasive carcinoma (BRCA).MethodsThe gene expression, methylation level, copy number, protein expression and patient survival data related to SOCS family members in BRCA patients were obtained from the following databases: Oncomine, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), PCViz, cBioPortal and Kaplan-Meier plotter. Correlation analyses, identification of interacting genes and construction of regulatory networks were performed by functional and pathway enrichment analyses, weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA).ResultsData related to 1109 BRCA tissues and 113 normal breast tissue samples were extracted from the TCGA database. SOCS2 and SOCS3 exhibited significantly lower mRNA expression levels in BRCA tissues than in normal tissues. BRCA patients with high mRNA levels of SOCS3 (p < 0.01) and SOCS4 (p < 0.05) were predicted to have significantly longer overall survival (OS) times. Multivariate analysis showed that SOCS3 was an independent prognostic factor for OS. High mRNA expression levels of SOCS2 (p < 0.001), SOCS3 (p < 0.001), and SOCS4 (p < 0.01), and a low expression level of SOCS5 (p < 0.001) were predicted to be significantly associated with better recurrence-free survival (RFS). Multivariate analysis showed that SOCS2 was an independent prognostic factor for RFS. Lower expression levels of SOCS2 and SOCS3 were observed in patients with tumors of more advanced clinical stage (p < 0.05). Functional and pathway enrichment analyses, together with WGCNA and GSEA, showed that SOCS3 and its interacting genes were significantly involved in the JAK-STAT signaling pathway, suggesting that JAK-STAT signaling might play a critical role in BRCA angiogenesis and development. Western blot results showed that overexpression of SOCS3 inhibited the activity of the JAK-STAT signaling pathway in vitro.ConclusionsSOCS family proteins play a very important role in BRCA. SOCS3 may be a prognostic factor and SOCS2 may be a potential therapeutic target in breast cancer.