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Purpose: To investigate whether longitudinal changes in multiparametric MRI can predict early response to neoadjuvant chemotherapy (NAC) for HER2-positive breast cancer (BC) and to further establish quantitative models based on these features., Methods: A total of 164 HER2-positive BC patients from three centers were included. MRI was performed at baseline and after two cycles of NAC (early post-NAC). Clinicopathological characteristics were enrolled. MRI features were evaluated at baseline and early post-NAC, as well as longitudinal changes in multiparametric MRI, including changes in the largest diameter (LD) of the tumor (ΔLD), apparent diffusion coefficient (ADC) values (ΔADC), and time-signal intensity curve (TIC) (ΔTIC). The patients were divided into a training set (n = 95), an internal validation set (n = 31), and an independent external validation set (n = 38). Univariate and multivariate logistic regression analyses were used to identify the independent indicators of pCR, which were then used to establish the clinicopathologic model and combined model. The AUC was used to evaluate the predictive power of the different models and calibration curves were used to evaluate the consistency of the prediction of pCR in different models. Additionally, decision curve analysis (DCA) was employed to determine the clinical usefulness of the different models., Results: Two models were enrolled in this study, including the clinicopathologic model and the combined model. The LD at early post-NAC (OR=0.913, 95 % CI=0.953-0.994 p = 0.026), ΔADC (OR=1.005, 95 % CI=1.005-1.008, p = 0.007), and ΔTIC (OR=3.974, 95 % CI=1.276-12.358, p = 0.017) were identified as the best predictors of NAC response. The combined model constructed by the combination of LD at early post-NAC, ΔADC, and ΔTIC showed good predictive performance in the training set (AUC=0.87), internal validation set (AUC=0.78), and external validation set (AUC=0.79), which performed better than the clinicopathologic model in all sets., Conclusions: The changes in multiparametric MRI can predict early treatment response for HER2-positive BC and may be helpful for individualized treatment planning., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Breast cancer (BC) is the most common cancer in women and is known for its tendency to spread to the bones, causing significant health issues and mortality. In this study, we aimed to investigate whether cryoprotective isoliquiritigenin-zein phosphatidylcholine nanoparticles (ISL@ZLH NPs) could inhibit BC-induced bone destruction and tumor metastasis in both in vitro and animal models. To evaluate the potential of ISL@ZLH NPs, we conducted various experiments. First, we assessed cell viability, colony formation, transwell migration, and wound healing assays to determine the impact of ISL@ZLH NPs on BC cell behavior. Western blotting, TRAP staining and ALP activity were performed to examine the effects of ISL@ZLH NPs on osteoclast formation induced by MDA-MB-231 cell-conditioned medium and RANKL treated RAW 264.7 cells. Furthermore, we assessed the therapeutic impact of ISL@ZLH NPs on tumor-induced bone destruction using a mouse model of BC bone metastasis. Treatment with ISL@ZLH NPs effectively suppressed BC cell proliferation, colony formation, and motility, reducing their ability to metastasize. ISL@ZLH NPs significantly inhibited osteoclast formation and the expression of factors associated with bone destruction in BC cells. Additionally, ISL@ZLH NPs suppressed JAK-STAT signaling in RAW264.7 cells. In the BCBM mouse model, ISL@ZLH NPs led to a significant reduction in osteolytic bone lesions compared to the control group. Histological analysis and TRAP staining confirmed that ISL@ZLH NPs preserved the integrity of bone structure, preventing invasive metastasis by confining tumor growth to the bone marrow cavity. Furthermore, ISL@ZLH NPs effectively suppressed tumor-induced osteoclastogenesis, a key process in BC-related bone destruction. Our findings demonstrate that ISL@ZLH NPs have the potential to inhibit BC-induced bone destruction and tumor metastasis by targeting JAK-STAT signaling pathways and suppressing tumor-induced osteoclastogenesis. These results underscore the therapeutic promise of ISL@ZLH NPs in managing BC metastasis to the bones., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Ductal carcinoma in situ with microinvasion (DCIS-MI) is a special type of breast cancer. It is an invasive lesion less than 1.0 mm in size related to simple ductal carcinoma in situ (DCIS). Lymph node metastasis (LNM) in DCIS-MI often indicates a poor prognosis. Therefore, the management of lymph nodes plays a vital role in the treatment strategy of DCIS-MI. Since DCIS-MI is often diagnosed by postoperative paraffin section and immunohistochemical detection, to obtain the best clinical benefits for such patients, we aim to establish and verify a nomogram to predict the possibility of lymph node metastasis in DCIS-MI patients and help preoperative or intraoperative clinical decision-making., Methods: A retrospective analysis of patients with DCIS-MI in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2019 was performed. The study cohort was randomly divided into a training cohort and a validation cohort at a ratio of 7:3. The risk factors were determined by univariate and multivariate logistic regression analyses in the training cohort, and a nomogram was constructed. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the nomogram in the training set and validation set. An independent data cohort was obtained from the Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB) for external validation., Results: This study included 3951 female patients from SEER with DCIS-MI, including 244 patients with regional lymph node metastasis, accounting for 6.18% of the total. An independent test set of 323 patients from SJTU-BCDB was used for external validation. According to the multifactorial logistic regression analysis results, age at diagnosis, ethnicity, grade, and surgical modality were included in the prediction model. The areas under the ROC curves (AUCs) were 0.739 (95% CI: 0.702~0.775), 0.732 (95% CI: 0.675~0.788), and 0.707 (95%CI: 0.607-0.807) in the training, validation and external test groups, suggesting that the column line graphs had excellent differentiation. The calibration curves slope was close to 1, and the model's predicted values were in good agreement with the actual values. The DCA curves showed good clinical utility., Conclusion: In this study, we constructed accurate and practical columnar maps with some clinical benefit to predict the likelihood of lymph node metastasis in patients with postoperatively diagnosed DCIS-MI and provide a reference value for specifying treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright: © 2024 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Non-alcoholic fatty liver disease (NAFLD) has been shown to influence breast cancer progression, but the underlying mechanisms remain unclear. In this study, we investigated the impact of NAFLD on breast cancer tumor growth and cell viability through the potential mediator, hepatic fibroblast growth factor 21 (FGF21). Both peritumoral and systemic administration of FGF21 promoted breast cancer tumor growth, while FGF21 knockout attenuated the tumor-promoting effects of the high-fat diet. Mechanistically, exogenous FGF21 treatment enhanced the anti-apoptotic ability of breast cancer cells through STAT3 and Akt/FoXO1 signaling pathways, and mitigated doxorubicin-induced cell death. Furthermore, we observed overexpression of FGF21 in tumor tissues from breast cancer patients, which was associated with poor prognosis. These findings suggest a novel role for FGF21 as an upregulated mediator in the context of NAFLD, promoting breast cancer development and highlighting its potential as a therapeutic target for cancer treatment., (© 2024. The Author(s).)

Background: Yishan formula (YSF) has a significant effect on the treatment of breast cancer, which can improve the quality of life and prolong the survival of patients with breast cancer; however, its mechanism of action is unknown., Objective: In this study, network pharmacology and molecular docking methods have been used to explore the potential pharmacological effects of the YSF, and the predicted targets have been validated by in vitro experiments., Methods: Active components and targets of the YSF were obtained from the TCMSP and Swiss target prediction website. Four databases, namely GeneCards, OMIM, TTD, and DisGeNET, were used to search for disease targets. The Cytoscape v3.9.0 software was utilized to draw the network of drug-component-target and selected core targets. DAVID database was used to analyze the biological functions and pathways of key targets. Finally, molecular docking and in vitro experiments have been used to verify the hub genes., Results: Through data collection from the database, 157 active components and 618 genes implicated in breast cancer were obtained and treated using the YSF. After screening, the main active components (kaempferol, quercetin, isorhamnetin, dinatin, luteolin, and tamarixetin) and key genes ( AKT1, TP53, TNF, IL6, EGFR, SRC, VEGFA, STAT3, MAPK3 , and JUN ) were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that the YSF could affect the progression of breast cancer by regulating biological processes, such as signal transduction, cell proliferation and apoptosis, protein phosphorylation, as well as PI3K-Akt, Rap1, MAPK, FOXO, HIF-1, and other related signaling pathways. Molecular docking suggested that IL6 with isorhamnetin, MAPK3 with kaempferol, and EGFR with luteolin have strong binding energy. The experiment further verified that YSF can control the development of breast cancer by inhibiting the expression of the hub genes., Conclusion: This study showed that resistance to breast cancer may be achieved by the synergy of multiple active components, target genes, and signal pathways, which can provide new avenues for breast cancer-targeted therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Breast cancer (BC) is one of the malignant diseases threatening the life and health of women worldwide. The CYP4B1 gene was abnormally expressed in BC and was associated with the prognosis of BC patients. This study aimed to explore the relationship between CYP4B1 single nucleotide polymorphisms (SNPs) and BC risk in Chinese women., Methods: A case-control study of 1,143 women (571 patients and 572 healthy individuals) was conducted. Rs2297813 G/T, rs12142787 G/A, and rs3766197 C/T in CYP4B1 were selected and genotyped by MassARRAY system. The relationships between these SNPs and the risk of BC were assessed by logistic regression analysis. In addition, multi-factor dimensionality reduction (MDR) was used to analyze SNP-SNP interactions., Results: CYP4B1 rs2297813 had a risk-increasing effect on BC in women with body mass index (BMI) ≤ 24 kg/m 2 (OR = 1.72, p = 0.026). CYP4B1 rs12142787 was associated with an increased BC risk in smokers (AA: OR = 1.32, p = 0.045). Among non-drinkers, rs2297813 (OR = 1.69, p = 0.009) and rs12142787 (OR = 1.51, p = 0.020) were related to an increased incidence of BC. CYP4B1 rs3766197 (OR = 1.61p = 0.031) was associated with a higher risk of advanced stages (III/IV stage) of BC. Besides, the contributions of CYP4B1 rs2297813 (OR = 1.55, p = 0.021) and rs12142787 (OR = 1.53, p = 0.033) to BC risk might be associated with more than one birth in patients with BC. The three-locus model consisting of rs2297813, rs12142787, and rs3766197 was regarded as the best predictive model for BC risk., Conclusion: CYP4B1 SNPs were associated with BC risk in Chinese women, especially in patients with BMI ≤ 24 kg/m 2 , smokers, non-drinkers, patients in advanced stages (III/IV stage), and patients who reproduced once. These findings shed light on the relationship between CYP4B1 SNPs and BC risk in Chinese women., (© 2023. The Author(s).)

Aim: To develop a simple and convenient method based on multiparametric magnetic resonance imaging (MRI) and clinical features to non-invasively predict tumour-infiltrating lymphocytes (TILs) in breast cancer (BC) and to explore the relationship between TIL levels and disease-free survival (DFS)., Materials and Methods: A total of 172 BC patients were enrolled between November 2017 and June 2021 in this retrospective study. The patients were divided into high (≥10%) and low (<10%) TIL groups. Clinicopathological data were collected. MRI features were reviewed by two radiologists. Predictors associated with TILs were determined by using multivariable logistic regression analyses. Kaplan-Meier survival curves based on TIL levels were used to estimate DFS., Results: A total of 102 patients with low TILs and 70 patients with high TILs were included in the study. Tumour size (odds ratio [OR], 1.040; 95% confidence interval [CI]: 1.006, 1.075; p=0.020), apparent diffusion coefficient (ADC; OR, 1.003; 95% CI: 1.001, 1.005; p=0.015), clinical axillary lymph node status (CALNS; OR, 3.222; 95% CI: 1.372,7.568; p=0.007), and enhancement pattern (OR, 0.284; 95% CI: 0.143, 0.563; p<0.001) were independently associated with TIL levels. These features were used in the ALSE model (where A is ADC, L is CALNS, S is size, and E is enhancement pattern). High TILs were associated with better DFS (p=0.016)., Conclusion: The ALSE model derived from multiparametric MRI and clinical features could non-invasively predict TIL levels in BC, and high TILs were associated with longer DFS, especially in human epidermal growth factor receptor 2 (HER2)-positive BC and triple-negative BC (TNBC)., (Copyright © 2023. Published by Elsevier Ltd.)

Aim: To develop an integrated model based on preoperative magnetic resonance imaging (MRI) features for predicting early recurrence in patients with triple-negative breast cancer (TNBC)., Materials and Methods: Women with TNBC who underwent breast MRI and surgery between 2009 and 2019 were evaluated retrospectively. Two breast radiologists reviewed MRI images independently based on the Breast Imaging Reporting and Data System Lexicon (BI-RADS), and classified the breast oedema scores on T2-weighted imaging (WI) as no oedema, peritumoural oedema, prepectoral oedema, or subcutaneous oedema. The relationship between disease-free survival (DFS) and MRI features was analysed by Cox regression, and a nomogram model was generated based on the results., Results: 150 patients with TNBC were included and divided into a training cohort (n=78) and validation cohort (n=72). MRI features including subcutaneous oedema and rim enhancement showed a tendency to worsen DFS in univariate analysis. Multivariate analysis showed that subcutaneous oedema (p=0.049, HR [95% confidence interval {CI} = 8.24 [1.01-67.52]) and rim enhancement (p=0.016, HR [95% CI] = 4.38 [1.32-14.54]) were independent predictors for DFS. In the nomogram, the areas under the curves (AUCs) of the training cohort was 0.808, and that of the validation cohort was 0.875., Conclusion: The presence of subcutaneous oedema or rim enhancement on preoperative breast MRI was shown to be a good predictor of poor survival outcomes in patients with TNBC., (Copyright © 2023. Published by Elsevier Ltd.)

BACKGROUND. Abbreviated protocols could allow wider adoption of MRI in patients undergoing breast cancer neoadjuvant chemotherapy (NAC). However, abbreviated MRI has been explored primarily in screening settings. OBJECTIVE. The purpose of this article was to compare diagnostic performance of abbreviated MRI and full-protocol MRI for evaluation of breast cancer NAC response, stratifying by radiologists' breast imaging expertise. METHODS. This retrospective study included 203 patients with breast cancer (mean age, 52.1 ± 11.2 [SD] years) from two hospitals who underwent MRI before NAC initiation and after NAC completion before surgical resection from March 2017 to April 2021. Abbreviated MRI was extracted from full-protocol MRI and included the axial T2-weighted sequence and precontrast and single early postcontrast T1-weighted sequences. Three general radiologists and three breast radiologists independently interpreted abbreviated and full-protocol MRI in separate sessions, identifying enhancing lesions to indicate residual tumor and measuring lesion size. The reference standard was presence and size of residual tumor on pathologic assessment of post-NAC surgical specimens. RESULTS. A total of 50 of 203 patients had pathologic complete response (pCR). Intraobserver and interobserver agreement for abbreviated and full-protocol MRI for general and breast radiologists ranged from substantial to nearly perfect (κ = 0.70-0.81). Abbreviated MRI compared with full-protocol MRI showed no significant difference for general radiologists in sensitivity (54.7% vs 57.3%, p > .99), specificity (92.8% vs 95.6%, p = .29), or accuracy (83.4% vs 86.2%, p = .30), nor for breast radiologists in sensitivity (60.0% vs 61.3%, p > .99), specificity (94.6% vs 97.4%, p = .22), or accuracy (86.0% vs 88.5%, p = .30). Sensitivity, specificity, and accuracy were not significantly different between protocols for any reader individually ( p > .05). Mean difference in residual tumor size on MRI relative to pathology for abbreviated protocol ranged for general radiologists from -0.19 to 0.03 mm and for breast radiologists from -0.15 to -0.05 mm, and for full protocol ranged for general radiologists from 0.57 to 0.65 mm and for breast radiologists from 0.66 to 0.79 mm. CONCLUSION. Abbreviated compared with full-protocol MRI showed similar intraobserver and interobserver agreement and no significant difference in diagnostic performance. Full-protocol MRI but not abbreviated MRI slightly overestimated pathologic tumor sizes. CLINICAL IMPACT. Abbreviated protocols may facilitate use of MRI for post-NAC response assessment by general and breast radiologists.

To evaluate the health-related quality-of-life (QOL) outcomes in surgical breast cancer survivors who received breast conservation therapy (BCT) compared to mastectomy, we utilized a systematic review to conduct observational studies of QOL in patients with breast cancer following breast conservation therapy from their inception until October 2021. The PubMed, the Cochrane Library, and the Web of Science databases were systematically searched to retrieve the observational studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were applied as an effect estimate and calculated using Stata 15 software. Nine studies comprising 2301 patients were included. The results showed that no significant differences compared to mastectomy were detected for global health status ( P =0.971 and P =0.613), physical function ( P =0.099), emotional function ( P =0.096), cognitive function ( P =0.377), social function ( P =0.602), sexual functioning ( P =0.072), and sexual enjoyment ( P =0.142), while role function ( P =0.036), body image ( P =0.000), and future perspective ( P =0.012) showed a significant difference for BCT when compared to mastectomy. When compared to breast reconstruction (BR), the BCT group was inferior at physical function ( P =0.002) and cognitive function ( P =0.040) but superior at body image ( P =0.001). When used the Functional Assessment of Cancer Therapy (FACT) tool, BCT has better results in physical function ( P =0.000), emotional function ( P =0.000), and social function ( P =0.000) than mastectomy. QOL outcomes after BCT were better than mastectomy in body image, future perspective, and role function. BCT may be an acceptable option in the study setting for breast cancer patients who pursue high QOL., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Yue Li et al.)

Objective: To use meta-analysis to systematically compare the efficacy and adverse reaction rates of albumin paclitaxel and docetaxel in the treatment of breast cancer., Methods: This study included Chinese and English literature studies on clinical controlled studies of albumin paclitaxel and docetaxel in the treatment of breast cancer by searching CNKI, Weipu, Wanfang, PubMed, Embase, and Cochrane Library. Two researchers participated in the screening of the literature, used the inclusion and exclusion criteria as reference indicators, extracted relevant data, and used the software RevMan5.3 to conduct quality evaluation and meta-analysis of the literature., Results: 4 literature stuides were retrieved that met the inclusion criteria, with 243 study subjects. The included literature had a lower risk of bias. Meta-analysis results showed that compared with the docetaxel group, the protein paclitaxel group had significant differences in objective effective rate (ORR) (OR = 1.56, 95% CI (0.80, 3.03), P =0.19), complete remission (CR) (OR = 1.79, 95% CI (0.96, 3.35), P =0.07), partial remission (PR) (OR = 0.88, 95% CI (0.53, 1.47), P =0.62), nausea (OR = 0.87, 95% CI (0.51, 1.74), P =0.84), and vomiting (OR = 0.62, 95% CI (0.45, 1.78) P =0.76). The reason may be that the number of literatures included in this study is small or the sample size is insufficient. However, it had an advantage in the incidence of neutropenia (OR = 0.38, 95% CI (0.16, 0.88), P =0.02), and the difference between the two groups was statistically significant., Conclusion: Albumin paclitaxel treatment can better reduce the incidence of neutropenia in breast cancer patients and is of great significance to the safety of breast cancer patients., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Huixin Xu et al.)

Background: There is limited knowledge about DCIS cellular composition and relationship with breast cancer events (BCE)., Methods: Immunofluorescence multiplexing (MxIF) was used to image and quantify 32 cellular biomarkers in FFPE DCIS tissue microarrays. Over 75,000 DCIS cells from 51 patients (median 9 years follow-up for non-BCE cases) were analysed for profiles predictive of BCE. K-means clustering was used to evaluate cellular co-expression of epithelial markers with ER and HER2., Results: Only ER, PR and HER2 significantly correlated with BCE. Cluster analysis identified 6 distinct cell groups with different levels of ER, Her2, cMET and SLC7A5. Clusters 1 and 3 were not significant. Clusters 2 and 4 (high ER/low HER2 and SLC7A5/mixed cMET) significantly correlated with low BCE risk (P = 0.001 and P = 0.034), while cluster 6 (high HER2/low ER, cMET and SLC7A5) correlated with increased risk (P = 0.018). Cluster 5 (similar to cluster 6, except high SLC7A5) trended towards significance (P = 0.072). A continuous expression score (Escore) based on these 4 clusters predicted likelihood of BCE (AUC = 0.79, log-rank test P = 5E-05; LOOCV AUC = 0.74, log-rank test P = 0.006)., Conclusion: Multiplexed spatial analysis of limited tissue is a novel method for biomarker analysis and predicting BCEs. Further validation of Escore is needed in a larger cohort.

Objective: To investigate the correlation between breast cancer magnetic resonance imaging features and immune molecular subtypes., Patients and Methods: A total of 129 breast cancer patients were selected as the research object. All the patients were diagnosed by histopathology. All of them had breast magnetic resonance imaging and examination data of immunohistochemical (IHC) ER, PR, HER-2, and Ki-67. The correlation of breast cancer magnetic resonance imaging features with different immune molecular subtypes was retrospectively analyzed., Results: Breast cancer is divided into different molecular subtypes. There were 72 cases with Luminal A type (55.81%), 20 cases with Luminal B type (15.50%), 14 cases with HER-2+ type (HER-2 type for over-expression) (10.85%), 23 cases with TNBC type (ER, PR and HER-2 were negative) (17.84%). The magnetic resonance imaging features of breast cancer were included, the post-enhanced morphology, margins, internal enhancement features, time-signal intensity curve (TIC) and molecular subtype expression of lesions were significantly correlated with the immune molecular subtypes (C=0.602, 0.439, 0.350 and 0.407, p=0.000, 0.000, 0.006 and 0.000). Lesion morphology: Luminal A type was mainly oval, accounting for 76.39% (55/76). Luminal B type and HER-2+ type was mainly irregular, accounting for 75.00% (15/20) and 64.29% (9/14) respectively. TNBC type was mainly shown as lobulation, accounting for 60.87% (14/23). Margin of the lesion: Luminal A type was mainly smooth margin, accounting for 73.61% (53/72). Luminal B type and TNBC type were mainly irregular margin, accounting for 70.00% (14/20) and 56.52% (13/23) respectively. The margin of HER-2+ type was mainly spiculation, accounting for 64.29% (9/14). The internal enhancement features: Luminal A type was mainly even enhancement, accounting for 62.50% (45/72). Luminal B type and HER-2+ type were mainly heterogeneous enhancement, accounting for 65.00% (13/20) and 64.29% (9/14) respectively. TNBC type was mainly annular enhancement, accounting for 73.91% (17/23). TIC type: Luminal A type was mainly Type II, accounting for 66.67% (48/72). Luminal B, HER-2+ type and TNBC type was mainly Type III, accounting for 70.00% (14/20), 64.29% (9/14) and 60.87% (14/23) respectively. The clinical signs include painless breast lumps, bloody breast discharge, and orange peel-like skin changes, nipple retraction and nipple elevation. There is no significant correlation between the above signs and the expression of molecular subtypes (C=0.014, 0.129, 0.154, 0.097 and 0.057, p=0.999, 0.533, 0.447, 0.747 and 0.935 respectively), the difference is not statistically significant (p>0.05)., Conclusions: The characteristics of breast cancer magnetic resonance imaging was certainly correlated with the expression of immune molecular subtypes. The breast cancer molecular subtypes can be predicted by the imaging signs, which can provide valuable information for preoperative neoadjuvant treatment of breast cancer.

Background: Immune cells have essential auxiliary functions and influence clinical outcomes in cancer, with high immune infiltration being associated with improved clinical outcomes and better response to treatment in breast cancer (BC). However, studies to date have not fully considered the tumor-infiltrating immune cell (TIIC) landscape in tumors. This study investigated potential biomarkers based on TIICs to improve prognosis and treatment effect in BC. Results: We enrolled 5112 patients for analysis and used cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT), a new computational algorithm, to quantify 22 TIICs in primary BC. From the results of univariate Cox regression, 12 immune cells were determined to be significantly related to the overall survival (OS) of BC patients. Furthermore, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were applied to construct an immune prognostic model based on six potential biomarkers. By dividing patients into low- and high-risk groups, a significant distinction in OS was found in the training cohort, with 20-year survival rates of 42.6% and 26.3%, respectively. Applying a similar protocol to validation and test cohorts, we found that OS was significantly shorter in the high-risk group than in the low-risk group, regardless of the molecular subtype of BC. Using the immune score model to predict the effect of BC patients to chemotherapy, the survival advantage for the low-risk group was evident among those who received chemotherapy, regardless of the chemotherapy regimen. In evaluating the predictive value of the nomogram, a decision curve showed better predictive accuracy than the standard tumor-node-metastasis (TNM) staging system. Conclusion: The immune cell infiltration-based immune score model can be effectively and efficiently used to predict the prognosis of BC patients as well as the effect of chemotherapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aim: To assess the cost-effectiveness of CYP2D6*10 genetic testing for the management of Chinese women with hormone receptor-positive (HR+) breast cancer treated with selective estrogen receptor modulator. Methods: A Markov model was developed to evaluate a total expected cost and an incremental cost-effectiveness ratio (ICER). Robustness of the model was addressed in one-way analyses and probabilistic sensitivity analysis. Results: The cost of strategies of tamoxifen, toremifene without genotyping and the strategy base on CYP2D6*10 genotype were $63,879.19, $90,156.60 and $95,021.41, and the quality-adjusted life years gained are 8.1588, 12.89687 and 13.85911, respectively. The incremental cost-effectiveness ratio of the CYP2D6*10 testing versus toremifene were 5,055.74221/quality-adjusted life year, respectively. Conclusion: CYP2D6*10 pharmacogenetic-guided selective estrogen receptor modulator can be a cost-effective strategy in the Chinese patients with hormone receptor-positive breast cancer.

Integrating protein-coding gene (PCG) with long noncoding RNA (lncRNA) expression profiles, our aim is to identify a multidimensional transcriptome model that can predict individual prognosis of patients with breast cancer (BRCA). After diverse bioinformatics and statistical analyses, we obtained gene expression profiles of 1,016 BRCA samples from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database, and constructed a prognostic signature, which is composed of four PCGs (TFCP2, LRRC75B, PROSER2, and STOML1) and one lncRNA (AL355592.1). In the training set, the multidimensional transcriptome signature could part patients with BRCA into two groups with different survival, defined as high- and low-risk group by Kaplan-Meier (KM) analysis (p < 0.001). In the other five validation datasets, the PCG-lncRNA signature showed a similar predictive performance in BRCA by KM (p < 0.05). The prognostic independence for the PCG-lncRNA model was verified by the multivariable Cox regression analysis. Because Chi-squared test showed the signature was associated with lymph node metastasis status, stratification analysis found that it could further subdivide lymph node metastasis status more precisely in BRCA. The function analysis suggested that the genes from the signature were associated with immunity-related pathways. In summary, we constructed a PCG-lncRNA signature, which could accurately predict survival in patients with BRCA., (© 2019 Wiley Periodicals, Inc.)

SUMO-specific Cysteine Proteases (SENPs) have involvement in the initiation and progression of human cancers. In the present study, we evaluated the association of SENPs polymorphism with susceptibility as well as clinicopathologic features and patients' response of breast cancer (BC) in a Chinese population.We genotyped SENP1 (rs61918808), SENP2 (rs6762208), SENP7 (rs61697963) by sequencing in a case-control study including 210 BC patients and 225 healthy volunteers. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assume the association strength.No significant association was found between polymorphism of the 3 SENPs and BC susceptibility. However, SENP1 rs61918808 (C>T) and SENP7 rs61697963 (A>C) was associated with HER-2 expression (P < .05). SENP2 rs6762208(C>A) was correlated with increasing risk of lymph node metastases (P < .05). Among the patients who received neoadjuvant chemotherapy, T allele and TT genotype of SENP1 rs61918808 were less likely to achieve pCR (P < .05).We first reported SENPs variants were not associated with BC risk in Chinese population, but presented specific effect on clinicopathological features of BC. Moreover, SENP1 rs61918808 may be a predictor for the clinical response in local advanced BC patients who received neoadjuvant chemotherapy.

Heterogeneous patterns of mutations and RNA expression have been well documented in invasive cancers. However, technological challenges have limited the ability to study heterogeneity of protein expression. This is particularly true for pre-invasive lesions such as ductal carcinoma in situ of the breast. Cell-level heterogeneity in ductal carcinoma in situ was analyzed in a single 5 μm tissue section using a multiplexed immunofluorescence analysis of 11 disease-related markers (EGFR, HER2, HER4, S6, pmTOR, CD44v6, SLC7A5 and CD10, CD4, CD8 and CD20, plus pan-cytokeratin, pan-cadherin, DAPI, and Na+K+ATPase for cell segmentation). Expression was quantified at cell level using a single-cell segmentation algorithm. K-means clustering was used to determine co-expression patterns of epithelial cell markers and immune markers. We document for the first time the presence of epithelial cell heterogeneity within ducts, between ducts and between patients with ductal carcinoma in situ. There was moderate heterogeneity in a distribution of eight clusters within each duct (average Shannon index 0.76; range 0-1.61). Furthermore, within each patient, the average Shannon index across all ducts ranged from 0.33 to 1.02 (s.d. 0.09-0.38). As the distribution of clusters within ducts was uneven, the analysis of eight ducts might be sufficient to represent all the clusters ie within- and between-duct heterogeneity. The pattern of epithelial cell clustering was associated with the presence and type of immune infiltrates, indicating a complex interaction between the epithelial tumor and immune system for each patient. This analysis also provides the first evidence that simultaneous analysis of both the epithelial and immune/stromal components might be necessary to understand the complex milieu in ductal carcinoma in situ lesions.

Many microRNAs (miRs) have been demonstrated to play promoting or tumor suppressive roles in human cancers including breast cancer. However, the molecular mechanism of miR-133a underlying the malignant progression of breast cancer still remains obscure. In the present study we observed that the expression of miR-133a was significantly downregulated in breast cancer tissues and cell lines, when compared with adjacent non-tumor tissues and normal breast cell line, respectively. Reduced miR-133a levels were significantly associated with advanced clinical stage, lymph node metastasis, as well as shorter survival time of patients with breast cancer. Restoration of miR-133a expression led to significant decrease in the proliferation, migration, and invasion of SK-BR-3 and MDA-MB-231 cells in vitro, as well as in tumor xenograft growth in nude mice. Luciferase reporter gene assay data identified LASP1 as a target gene of miR-133a, and the expression of LASP1 was negatively regulated by miR-133a in breast cancer cells. LASP1 was significantly upregulated in breast cancer tissues and cell lines, and its upregulation was significantly associated with disease progression. siRNA-induced LASP1 downregulation caused a significant reduction in breast cancer cell proliferation, migration and invasion. Furthermore, overexpression of LASP1 impaired the suppressive effects of miR-133a upregulation on the proliferation, migration and invasion of SK-BR-3 and MDA-MB-231 cells. In summary, the present study demonstrates that miR-133a acts as a tumor suppressor in breast cancer partly at least via targeting LASP1, and thus suggests that the miR-133a/LASP1 axis may become a potential therapeutic target for breast cancer.

Recent advances indicate that cancer‑associated fibroblasts (CAFs) play a key role in cancer progression by contributing to invasion, metastasis and angiogenesis. Solid tumors often experience low oxygen tension environments, which induce gene expression changes and biological features leading to poor outcomes. The G-protein estrogen receptor (GPER) exhibits a stimulatory role in diverse types of cancer cells and in CAFs under hypoxic conditions. We investigated the role of CAFs and hypoxia in breast cancer aggressiveness, and examined the effect of GPER in CAFs on hypoxia-driven breast cancer progression. The results showed that hypoxia upregulated HIF-1α, GPER and α-SMA expression in CAFs, and induced the secretion of Interleukin-6 (IL-6), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) in CAFs. However, GPER silencing abrogated the above hypoxia-driven cytokine expression in CAFs. Moreover, knockdown of GPER in CAFs suppressed breast cancer cell invasion induced by CAF conditioned media (CM). Furthermore, GPER silencing in CAFs inhibited hypoxia-increased CTGF expression in CAFs and breast cancer cells cultured with CM from CAFs under hypoxic conditions. In addition, CTGF is responsible for the observed effects of GPER on CAFs activation and breast cancer invasion. Our findings further extend the molecular mechanisms through which the tumor microenvironment may contribute to cancer progression.

Limitations on the number of unique protein and DNA molecules that can be characterized microscopically in a single tissue specimen impede advances in understanding the biological basis of health and disease. Here we present a multiplexed fluorescence microscopy method (MxIF) for quantitative, single-cell, and subcellular characterization of multiple analytes in formalin-fixed paraffin-embedded tissue. Chemical inactivation of fluorescent dyes after each image acquisition round allows reuse of common dyes in iterative staining and imaging cycles. The mild inactivation chemistry is compatible with total and phosphoprotein detection, as well as DNA FISH. Accurate computational registration of sequential images is achieved by aligning nuclear counterstain-derived fiducial points. Individual cells, plasma membrane, cytoplasm, nucleus, tumor, and stromal regions are segmented to achieve cellular and subcellular quantification of multiplexed targets. In a comparison of pathologist scoring of diaminobenzidine staining of serial sections and automated MxIF scoring of a single section, human epidermal growth factor receptor 2, estrogen receptor, p53, and androgen receptor staining by diaminobenzidine and MxIF methods yielded similar results. Single-cell staining patterns of 61 protein antigens by MxIF in 747 colorectal cancer subjects reveals extensive tumor heterogeneity, and cluster analysis of divergent signaling through ERK1/2, S6 kinase 1, and 4E binding protein 1 provides insights into the spatial organization of mechanistic target of rapamycin and MAPK signal transduction. Our results suggest MxIF should be broadly applicable to problems in the fields of basic biological research, drug discovery and development, and clinical diagnostics.

Dendritic cell (DC)/tumor cell fusion vaccine has been revealed as a promising tool for the antitumor immunotherapy. Previous research has shown that fusion hybrids of human DCs and autologous tumor cells can induce cytotoxic T lymphocyte (CTL) responses against autologous tumor cells in animal models and human clinical trials. However, a major restriction factor for the clinical use is the difficulty for preparation of sufficient amount of autologous tumor cells especially for the patients with metastasis cancer whose primary tumor lesion is not clear or has been resected. In this study, allogeneic breast cancer cell line MCF-7 cells were electrofused to autologous DCs from patient with breast cancer as a strategy to deliver shared breast cancer antigens to DCs. Fusion cells generated by autologous DCs and allogeneic MCF-7 were able to induce autologous T lymphocytes proliferation, high levels of IFN-gamma production and CTL responses. CTLs induced by DCs/allogeneic MCF-7 fusion cells were able to kill autologous breast cancer cells in an antigen specific and HLA restriction manner. Our study may provide the experiment basis for the use of allogeneic breast cancer cell line in the DC/tumor cell fusion cell vaccination strategy.

Objectives: To study the relation between exfoliated tumor cells in operative wound and clinical pathologic classification and to provide theory for killing exfoliated tumor cells in operation., Method: Washing liquid cytology examination of the operative wound was done in 262 patients with breast tumor. The relation between cytology examination and pathological classification was analyzed., Results: In the 262 patients, exfoliated tumor cells were found in 63 patients, (24%). The detection rate in patients with I, II, III and IV stage was 5.3%, 27.1%, 79.3% and 100% respectively; The rate for T(1), T(2), T(3) stage was 6.1%, 18.9% and 51.3% respectively. The detection rate was 58.6% when the number of metastasis lymph node beyond 3; the rate was 14.3% and 14.1% respectively when the number below 3 or no lymphatic metastasis., Conclusion: The detection rate of exfoliated tumor cells is related to tumor advance, and it is necessary to kill exfoliated tumor cells in operation.