An advanced machine learning method for simultaneous breast cancer risk prediction and risk ranking in Chinese population: A prospective cohort and modeling study.

BACKGROUND: Breast cancer (BC) risk-stratification tools for Asian women that are highly accurate and can provide improved interpretation ability are lacking. We aimed to develop risk-stratification models to predict long- and short-term BC risk among Chinese women and to simultaneously rank potential non-experimental risk factors. METHODS: The Breast Cancer Cohort Study in Chinese Women, a large ongoing prospective dynamic cohort study, includes 122,058 women aged 25-70 years from the eastern part of China. We developed multiple machine-learning risk prediction models using parametric models (penalized logistic regression, bootstrap, and ensemble learning), which were the short-term ensemble penalized logistic regression (EPLR) risk prediction model and the ensemble penalized long-term (EPLT) risk prediction model to estimate BC risk. The models were assessed based on calibration and discrimination, and following this assessment, they were externally validated in new study participants from 2017 to 2020. RESULTS: The AUC values of the short-term EPLR risk prediction model were 0.800 for the internal validation and 0.751 for the external validation set. For the long-term EPLT risk prediction model, the area under the receiver operating characteristic curve was 0.692 and 0.760 in internal and external validations, respectively. The net reclassification improvement index of the EPLT relative to the Gail and the Han Chinese Breast Cancer Prediction Model (HCBCP) models for external validation was 0.193 and 0.233, respectively, indicating that the EPLT model has higher classification accuracy. CONCLUSIONS: We developed the EPLR and EPLT models to screen populations with a high risk of developing BC. These can serve as useful tools to aid in risk-stratified screening and BC prevention.

Genomic and transcriptomic analysis of breast cancer identifies novel signatures associated with response to neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity. METHODS: We performed whole-exome and RNA sequencing on 233 samples (including matched pre- and post-treatment tumors) from 50 BC patients with rigorously defined responses to NAC and analyzed changes in the multi-omics landscape. Molecular features associated with NAC response were identified and validated in a larger internal, and two external validation cohorts, as well as in vitro experiments. RESULTS: The most frequently altered genes were TP53, TTN, and MUC16 in both pre- and post-treatment tumors. In comparison with pre-treatment tumors, there was a significant decrease in C > A transversion mutations in post-treatment tumors (P = 0.020). NAC significantly decreased the mutation rate (P = 0.006) of the DNA repair pathway and gene expression levels (FDR = 0.007) in this pathway. NAC also significantly changed the expression level of immune checkpoint genes and the abundance of tumor-infiltrating immune and stroma cells, including B cells, activated dendritic cells, γδT cells, M2 macrophages and endothelial cells. Furthermore, there was a higher rate of C > T substitutions in NAC nonresponsive tumors than responsive ones, especially when the substitution site was flanked by C and G. Importantly, there was a unique amplified region at 8p11.23 (containing ADGRA2 and ADRB3) and a deleted region at 3p13 (harboring FOXP1) in NAC nonresponsive and responsive tumors, respectively. Particularly, the CDKAL1 missense variant P409L (p.Pro409Leu, c.1226C > T) decreased BC cell sensitivity to docetaxel, and ADGRA2 or ADRB3 gene amplifications were associated with worse NAC response and poor prognosis in BC patients. CONCLUSIONS: Our study has revealed genomic and transcriptomic landscape changes following NAC in BC, and identified novel biomarkers (CDKAL1P409L, ADGRA2 and ADRB3) underlying chemotherapy resistance and poor prognosis, which could guide the development of personalized treatments for BC.

Efficacy and safety of rifampicin-based triple therapy for non-puerperal mastitis: A single-arm, open-label, prospective clinical trial.

OBJECTIVES: To assess the efficacy and safety of rifampicin-based triple therapy (rifampicin, isoniazid, and ethambutol) for treating NPM. METHODS: This single-center, single-arm, prospective clinical trial was conducted at the Second Hospital of Shandong University (Jinan, China). Patients with pathologically diagnosed granulomatous lobular mastitis and periductal mastitis received triple drugs, i.e., rifampicin (450 mg/day), isoniazid (300 mg/day), and ethambutol (15 mg/kg/day), until complete response or the investigator decided to discontinue treatment. The primary endpoint was the complete response rate (CRR) assessed by the investigator. The secondary endpoints included the overall remission rate (ORR), recurrence rate (RR), and safety. RESULTS: A total of 218 patients were enrolled in the study between January 1, 2013 and October 31, 2020. With a median follow-up time of 48 months, the CRR and the ORR were 78.44% and 94.04%, respectively. While 13 patients (5.96%) demonstrated no response and 19 relapsed (8.72%). Adverse events (AEs) were not common. The most common AEs during treatment were liver dysfunction (1.83%), gastrointestinal reactions (1.83%), fatigue (1.83%), erythema (1.38%), and menstrual disorders (0.92%). CONCLUSION: Rifampicin, isoniazid, and ethambutol demonstrated promising response rates with acceptable safety profiles in patients with NPM. Further confirmatory trial is warranted in the future. TRIAL REGISTRATION: The study was approved by the Ethics Committee of the Second Hospital of Shandong University and retrospectively registered at the China Clinical Trial Registration Center (registration number: ChiCTR2100049591).

Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: The phase I/II first-in-human MATINS trial.

Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%-40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.

Enhanced mechanical and functional properties of chitosan/polyvinyl alcohol/hydroxypropyl methylcellulose/alizarin composite film by incorporating cinnamon essential oil and tea polyphenols.

In this study, cinnamon essential oil and tea polyphenols were added to chitosan/ polyvinyl alcohol/ hydroxypropyl methylcellulose/ alizarin composite films to enhance their mechanical and functional properties. Their addition to the composite films enhanced their antibacterial and antioxidant properties and significantly improved its elongation at break (p < 0.05). Cinnamon essential oil reduced the water vapor permeability, water content, and water solubility of composite films and improved their transparency. The composite films with additive exhibited excellent UV-barrier ability and pH responsivity. Fourier Transform infrared spectroscopy and X-Ray Diffraction analyses confirmed hydrogen bond formation between the polymer molecules and additives. The results of Scanning Electron Microscope-Focused Ion Beam revealed improved surface and cross-section morphology of the films, leading to the generation of a cross-linked structure. Thermogravimetric and differential scanning calorimetry analysis indicated enhanced thermal stability of the composite films upon cinnamon essential oil addition. Analysis of storage quality indicators (TBARS value, TVC, and TVB-N) revealed that the composite films could prolong the freshness of surimi. The incorporation of cinnamon essential oil and tea polyphenols into the composite films has demonstrated significant potential as an effective and natural alternative for active food packaging.

The effectiveness of needle aspiration versus traditional incision and drainage in the treatment of breast abscess: a meta-analysis.

BACKGROUND: Breast abscess is a common and intractable clinical condition and the use of needle aspiration (NA) or incision and drainage (ID) in treatment is controversial. This meta-analysis aimed to systematically compare the clinical effectiveness of NA and ID in treating breast abscesses. METHODS: The Web of Science, ScienceDirect, PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure, and Wanfang Data were searched for randomized controlled trials (RCTs) published from inception to January 7, 2022. The ROB-2 tool assessed risk of bias; the GRADE methodology rated certainty in outcomes; and Stata 16.0 performed data analyses. RESULTS: Nine RCTs were included, including 703 patients. The results showed there was no significant difference in cure rate between the two groups (relative risk [RR] = 0.96, 95% confidence interval [CI] [0.86, 1.07]; p = .469), and after subgroup analysis, we found that it was not related to the use of ultrasound guidance or not. There was no significant difference in the recurrence rate (RR = 0.68, 95% CI [0.35, 1.30]; p = .241). Furthermore, the NA group was associated with shorter healing time (weighted mean differences = -11.02, 95% CI [-15.14, -6.90]; p < .001), lower incidence of breast fistula (RR = 0.21, 95% CI [0.06, 0.72]; p = .013), lower interrupted breastfeeding rate (RR = 0.28, 95% CI [0.20, 0.39]; p < .001), and higher satisfaction rate of appearance (RR = 1.51, 95% CI [1.03-2.21]; p = .035). CONCLUSION: NA has better advantages in terms of healing time, avoidance of breast fistula, continuous breastfeeding, and patient satisfaction. Although NA and ID have similar cure and recurrence rates, NA, with or without ultrasound guidance, could be used as a first-line treatment for breast abscesses. Patients with large volumes, multicompartmental abscesses, or those who have been ineffective against multiple NA, should be considered for ID.KEY MESSAGESBreast abscess is a common and intractable clinical condition in general surgery.Compared with ID for breast abscesses, NA has better advantages in terms of healing time, avoidance of breast fistula, continuous breastfeeding, and patient satisfaction and could be used as a first-line treatment for breast abscesses.Patients with large volumes, multicompartmental abscesses, or those who have been ineffective against multiple NA, should be considered for ID.

Depressive Symptoms and Sleep Duration as Risk Factors for Breast Cancer - China, 2020.

What is already known about this topic?: Psychological and lifestyle factors are known to potentially play a significant role in the development of breast cancer. However, current evidence-based studies present controversial findings on the associations between depression, sleep duration, and breast cancer risk. What is added by this report?: This study investigated the potential risk factors of depressive symptoms and short sleep duration for breast cancer within the Breast Cancer Cohort Study in Chinese Women. The findings revealed that women experiencing depressive symptoms and short sleep duration exhibited a heightened risk of developing breast cancer, particularly among the older population. What are the implications for public health practice?: Public policy ought to prioritize early health education interventions targeting psychological factors in order to facilitate the prevention of breast cancer.

Using machine learning to identify gene interaction networks associated with breast cancer.

BACKGROUND: Breast cancer (BC) is one of the most prevalent cancers worldwide but its etiology remains unclear. Obesity is recognized as a risk factor for BC, and many obesity-related genes may be involved in its occurrence and development. Research assessing the complex genetic mechanisms of BC should not only consider the effect of a single gene on the disease, but also focus on the interaction between genes. This study sought to construct a gene interaction network to identify potential pathogenic BC genes. METHODS: The study included 953 BC patients and 963 control individuals. Chi-square analysis was used to assess the correlation between demographic characteristics and BC. The joint density-based non-parametric differential interaction network analysis and classification (JDINAC) was used to build a BC gene interaction network using single nucleotide polymorphisms (SNP). The odds ratio (OR) and 95% confidence interval (95% CI) of hub gene SNPs were evaluated using a logistic regression model. To assess reliability, the hub genes were quantified by edgeR program using BC RNA-seq data from The Cancer Genome Atlas (TCGA) and identical edges were verified by logistic regression using UK Biobank datasets. Go and KEGG enrichment analysis were used to explore the biological functions of interactive genes. RESULTS: Body mass index (BMI) and menopause are important risk factors for BC. After adjusting for potential confounding factors, the BC gene interaction network was identified using JDINAC. LEP, LEPR, XRCC6, and RETN were identified as hub genes and both hub genes and edges were verified. LEPR genetic polymorphisms (rs1137101 and rs4655555) were also significantly associated with BC. Enrichment analysis showed that the identified genes were mainly involved in energy regulation and fat-related signaling pathways. CONCLUSION: We explored the interaction network of genes derived from SNP data in BC progression. Gene interaction networks provide new insight into the underlying mechanisms of BC.

The Impact of Reproductive Factors on the Risk of Breast Cancer by ER/PR and HER2: A Multicenter Case-Control Study in Northern and Eastern China.

BACKGROUND: Previous studies have suggested that reproductive factors are associated with breast cancer risk. Breast cancer subtypes have distinct natural characteristics and may also have unique risk profiles. The purpose of this study was to determine whether reproductive factors affect the risk of breast cancer by estrogen receptor (ER)/progesterone receptor (PR) and HER2 status. METHODS: A multicenter, case-control study was conducted. There were 1170 breast cancer patients and 1170 age- and hospital-matched females included in the analysis. Self-reported data were collected about lifestyle behaviors, including reproductive factors. Breast cancer cases were categorized subtypes according to ER, PR, and HER2 expression as HR- positive, HER2-enriched, and triple negative breast cancer (TNBC). Multivariable logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Having ≤1 child increased risk of HR-positive breast cancer (OR 1.882; 95%CI 1.29-2.74), especially in the premenopausal group (OR 2.212; 95%CI 1.23-3.99). Compared with women who first gave birth after age 30 years, earlier age at first birth decreased the risk of HR-positive breast cancer (≤23 years: OR 0.209; 95%CI 0.14-0.30; 24-29 years: OR 0.256; 95%CI 0.18-0.36; P < .001). Compared with those who had an average breastfed/birth period of more than 2 years, those with an average period less than 6 months had an elevated risk of all subtypes (HR positive: OR 2.690; 95%CI 1.71-4.16, P < .001; HER2-enriched: OR 3.779; 95%CI, 1.62-8.79, P = .001; TNBC: OR 2.564; 95%CI 1.11-5.94, P = .022). For postmenopausal patients, shorter period of lifetime menstrual cycles (≤30 years) had an obviously decreased risk in HR-positive cases (OR 0.397; 95%CI 0.22-0.71), while there was no similar appearance in other molecular subtypes. CONCLUSION: The results suggest that reproductive behaviors affect risk of breast cancer differently according to ER/PR and HER2 status.

Single-Nucleotide Polymorphisms in LEP and LEPR Associated With Breast Cancer Risk: Results From a Multicenter Case-Control Study in Chinese Females.

BACKGROUND: Leptin (LEP) plays a physiological role through its specific receptor (LEPR) and is involved in the occurrence and development of breast cancer. Our current study aimed at determining the influence of single-nucleotide polymorphisms (SNPs) in the genes coding for LEP and LEPR on breast cancer risk. METHODS: In the present study, 963 breast cancer cases and 953 controls were enrolled. Five SNPs of LEP and two of LEPR were chosen to evaluate the correlation of selected SNPs with breast cancer susceptibility among women in northern and eastern China. Analyses were further stratified by body mass index (BMI), waist-hip rate (WHR), estrogen receptor, and progesterone receptor status. The expression patterns of risk variant-associated genes were detected by expression quantitative trait locus (eQTL) analysis with eQTLGen and The Cancer Genome Atlas database. RESULTS: There were significant differences between breast cancer cases and control groups in the menopausal status and family history of breast cancer. Two SNPs (rs1137101 and rs4655555) of the LEPR gene decreased overall breast cancer risk, and other five SNPs showed no significant association with breast cancer risk. rs1137101 (GA vs. GG; adjusted OR = 0.719, 95% CI = 0.578-0.894, p = 0.003) and rs4655555 (TT vs. AA; adjusted OR = 0.574, 95% CI = 0.377-0.873, p = 0.009) significantly decreased breast cancer risk after Bonferroni correction for multiple testing. In subgroup analyses, the GA and GA + AA genotypes of LEPR rs1137101 associated with decreased breast cancer risk in the subgroup of BMI ≤ 24 kg/m2 or WHR ≥ 0.85 after Bonferroni correction. Furthermore, we found that the expressions of rs4655555-associated gene LEPR and leptin receptor overlapping transcript (LEPROT) were upregulated in breast cancer tumor tissues compared with adjacent normal tissues, and a higher expression of LEPR in tumor tissues was correlated with poor prognosis of breast cancer patients using The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) data. CONCLUSION: Our study demonstrated that the polymorphisms rs1137101 and rs4655555 located in the LEPR gene decreased breast cancer risk in Chinese females, which might be a research-worthy bio-diagnostic marker and applied for early prediction and risk assessment of breast cancer.

Prognostic value of gamma-interferon-inducible lysosomal thiol reductase expression in female patients diagnosed with breast cancer.

Because of the high heterogeneity of breast cancer outcome, identification of novel prognostic biomarkers is critical to improve patient stratification and guide precise treatment. We examined the prognostic value of gamma-interferon-inducible lysosomal thiol reductase (GILT) expression in a training set of 416 breast cancer patients and a validation set of 210 patients, and performed functional studies to investigate the functions and underlying mechanisms of GILT on breast cancer prognosis. Our results indicated that high GILT expression in breast cancer cells was associated with improved disease-free survival (DFS; hazard ratio [HR] = 0.189, 95% confidence interval [CI]: 0.099-0.361) and breast cancer-specific survival (BCSS; HR = 0.187, 95% CI: 0.080-0.437) of breast cancer patients both in the training set and the external validation set (HR = 0.453, 95% CI: 0.235-0.873 for DFS, HR = 0.488, 95% CI: 0.245-0.970 for BCSS). In vitro and in vivo studies showed that GILT overexpression inhibited breast cancer cells proliferation, invasion, migration and tumor formation in nude mice and increased sensitivity of breast cancer cells to standard treatment. Proteomics analysis indicated that GILT inhibited reactive oxygen species (ROS) and autophagy activation in breast cancer cells, and GILT overexpression-mediated tumor growth was further enhanced in the presence of autophagy or ROS inhibitors. Our results demonstrate that GILT expression can be effectively used to predict the prognosis and guide treatment strategies of breast cancer patients.

Worldwide review with meta-analysis of women's awareness about breast cancer.

OBJECTIVE: To summarize the awareness levels of breast cancer (BC) worldwide and investigate factors associated with BC awareness to determine differences in awareness between China and other countries. METHODS: This systematic review followed the PRISMA guidelines and included 92 articles up to July, 2021. We calculated percentages for BC awareness levels and conducted subgroup analysis and cumulative meta-analysis. RESULTS: A total 84% (95% confidence interval [95%CI]: 78-90%) of women knew about BC; however, only 51% (95%CI: 37-66%) and 40% (95%CI: 24-56%) of women were aware of BC symptoms and BC risk factors, respectively. The most commonly known BC symptom was breast lump (71%, 95%CI: 62-80%), and BC family history was the most well-known BC risk factor (61%, 95%CI: 54-69%). Subgroup analysis showed lower awareness levels among Chinese and Asian women than women from other countries. Cumulative meta-analysis showed no obvious progress in BC awareness levels over time. We investigated 15 awareness-related factors, the most frequent of which were education level (61.8%), occupation (29.4%), and age (26.5%). CONCLUSION: BC awareness levels remain low. Improving BC awareness is critical, especially in developing countries. PRACTICE IMPLICATIONS: Effective education programs are urgently needed to improve women's BC awareness.

XRCC5/6 polymorphisms and their interactions with smoking, alcohol consumption, and sleep satisfaction in breast cancer risk: A Chinese multi-center study.

BACKGROUND: X-ray repair cross-complementary 5 (XRCC5) and 6 (XRCC6) are critical for DNA repair. Few studies have assessed their association with breast cancer risk, and related gene-environment interactions remain poorly understood. This study aimed to determine the influence of XRCC5/6 polymorphisms on breast cancer risk, and their interactions with cigarette smoking, alcohol consumption, and sleep satisfaction. METHODS: The study included 1039 patients with breast cancer and 1040 controls. Four single-nucleotide polymorphisms of XRCC5 and two of XRCC6 were genotyped. Information about smoking, alcohol consumption, and sleep satisfaction was collected through questionnaires. Odds ratios (OR) and related 95% confidence intervals (95% CI) were assessed using unconditional logistic regression models. Gene-environment interactions were analyzed using logistic regression with multiplicative interaction models. RESULTS: XRCC5 rs16855458 was associated with increased breast cancer risk in the co-dominant (ptrend  = 0.003) and dominant (CA + AA vs. CC, OR = 1.29, 95% CI = 1.07-1.56, p = 0.008) genetic models after Bonferroni correction. The CG + GG genotype of XRCC6 rs2267437 was associated with an increased risk of estrogen receptor-negative/progesterone receptor-negative (ER-/PR-) breast cancer (CG + GG vs. CC: OR = 1.54, 95% CI = 1.12-2.13, p = 0.008) after Bonferroni correction. Moreover, an antagonistic interaction between XRCC5 rs16855458 and alcohol consumption (pinteraction  = 0.017), and a synergistic interaction between XRCC6 rs2267437 and sleep satisfaction were associated with breast cancer risk (pinteraction  = 0.0497). However, these interactions became insignificant after Bonferroni correction. CONCLUSION: XRCC5 rs16855458 was associated with breast cancer risk, and XRCC6 rs2267437 was associated with the risk of ER-/PR- breast cancer. Breast cancer risk associated with XRCC5 and XRCC6 polymorphisms might vary according to alcohol consumption and sleep satisfaction, respectively, and merit further investigation.

Relationship Between Lifestyle Habits and Health-Related Quality of Life of Recently Diagnosed Breast Cancer Patients: A Comparison Between Younger and Older Women in China.

Objective: The aim of this study was to evaluate the relationship between lifestyle habits and health-related quality of life (HRQoL) among different ages who were initially diagnosed with breast cancer (within the first 2 weeks) and to determine the contribution of lifestyle habits factors on HRQoL. Methods: Patients with breast cancer were recruited from 22 hospitals in 11 provinces or municipalities in northern and eastern China. The Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) was used to measure HRQoL. Chi-square test, ANOVA, and multivariable generalized linear models were conducted to identify the differences in HRQoL between two age groups (age <50 years and ≥50 years) and to evaluate the contribution of lifestyle habits factors on HRQoL of patients with breast cancer. Results: About 1,199 eligible patients with breast cancer were used for analysis. Younger women (aged <50 years) appeared to show lower scores than older women (aged ≥50 years) in HRQoL subscales, including emotional well-being (p = 0.003), functional well-being (p = 0.006), breast cancer subscale (p = 0.038), and FACT-B Total scores (p = 0.028). Tea and alcohol consumption and being very satisfied with sleep and current life were the strongest predictors of higher HRQoL in younger group. Meanwhile, no coffee consumption, frequent participation in physical activities, high sleep satisfaction, and current life satisfaction were the key predictors of higher HRQoL in older women with breast cancer. Conclusion: The relationship of the nine lifestyle habit items with HRQoL differed among younger and older women. The associated variable of low HRQoL can help clinicians take intervention early in order to improve the prognosis of patients with breast cancer.

Comparison of Conservative versus Surgical Treatment Protocols in Treating Idiopathic Granulomatous Mastitis: A Meta-Analysis.

BACKGROUND: Idiopathic granulomatous mastitis (IGM) is a rare, benign breast disease without any definitive therapeutic strategy. It is controversial whether to use conservative or surgical treatment of IGM and high-level evidence-based medicine data are lacking. The purpose of this study was to systemically evaluate the clinical effectiveness of the conservative versus surgical treatment for IGM. METHODS: In this meta-analysis, we searched PubMed, EMbase, ScienceDirect, and Web of Science for comparative studies about the conservative versus surgical treatment of IGM. Two researchers independently identified reports and extracted data. We used Stata 11 for data analysis. A meta-analysis was performed to investigate the differences in the recurrence rate of conservative and surgical treatment using a random effects model. RESULTS: A total of 10 studies involving 1,101 patients were included. The results demonstrated that there was no significant difference in the recurrence rate among patients who were treated by nonsurgical therapy and surgical treatment. No publication bias was detected. CONCLUSION: This meta-analysis demonstrates that both the conservative and surgical treatment approaches have appropriate efficacy in IGM treatment and relapse. Further randomized controlled trials with longer follow-up periods are required to confirm the advantages of each approach.

Adipocyte-derived SFRP5 inhibits breast cancer cells migration and invasion through Wnt and epithelial-mesenchymal transition signaling pathways.

OBJECTIVE: Obesity is closely associated with metastasis in breast cancer patients. Secreted frizzled-related protein 5 (SFRP5), one of the novel adipokines with anti-inflammatory properties, is associated with obesity. This study aims to study the role of SFRP5 in the crosstalk between obesity and breast cancer metastasis and identify the underlying mechanism. METHODS: 3T3-L1 pre-adipocytes were differentiated to mature adipocytes and a hypertrophic adipocyte model was induced with palmitic acid (PA). Cell motility was measured in MDA-MB-231 and MCF-7 breast cancer cells co-cultured with adipocytes conditioned medium (CM) with or without SFRP5 protein. Wnt and epithelial-mesenchymal transition (EMT) signal pathways were investigated by western blot. Circulating SFRP5 level in 218 breast cancer patients and the association with clinicopathologic characteristics of breast cancer were further determined. Online databases ENCORI and PREDICT Plus were used to exam the link between SFRP5 and prognosis. RESULTS: Reduced SFRP5 level was detected in the hypertrophic adipocyte model. Recombinant SFRP5 protein inhibited MDA-MB-231 and MCF-7 cells invasion and migration induced by PA-treated adipocyte CM, and SFRP5 inhibition by specific antibody reversed the effect of SFRP5. Furthermore, SFRP5 significantly inhibited Wnt and downstream EMT in breast cancer cells. Low circulating SFRP5 level correlated with body mass index (BMI), lymph node (LN) metastasis, TNM stage and high Ki67 expression in breast cancer patients. Increased SFRP5 level was associated with favorable predicted survival. Kaplan-Meier curves showed high SFRP5 level in tumor tissue was associated with better outcome of breast cancer patients. CONCLUSIONS: Our findings demonstrated SFRP5 is a vital adipokine that mediates the crosslink between obesity and the metastatic potential of breast cancer. Promotion of SFRP5 expression in the adipose microenvironment may represent a novel approach for preventing breast cancer metastasis.

Erratum: Addendum: Metabolic Syndrome, and Particularly the Hypertriglyceridemic-Waist Phenotype, Increases Breast Cancer Risk, and Adiponectin Is a Potential Mechanism: A Case-Control Study in Chinese Women.

[This corrects the article DOI: 10.3389/fendo.2019.00905.].

Higher frequency of dairy intake is associated with a reduced risk of breast cancer: Results from a case-control study in Northern and Eastern China.

The association between dairy intake and breast cancer risk has not been well investigated, especially in the Chinese population. This study aimed to examine the association between the weekly frequency of dairy intake and the risk of breast cancer among women in Northern and Eastern China, and to investigate whether the association varied by hormone receptor status. A total of 1,286 cases of breast cancer and 1,461 controls were enrolled in this study. Dairy intake was obtained using a food-frequency questionnaire (FFQ). Frequency of dairy intake per week was divided into four categories (<1 day/week, 1-2 days/week, 3-4 days/week and 5-7 days/week). Unconditional multivariate logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). Stratified analyses were performed by residence, age, and education level. Separate analyses were also conducted for different estrogen receptor (ER) and progesterone receptor (PR) status. This analysis revealed that weekly frequency of dairy intake was strongly inversely associated with breast cancer risk, with an adjusted OR for intake 5-7 days/week of 0.53 (95% CI=0.39-0.72, P<0.001 for trend). In the stratified analyses, women who consumed dairy 5-7 days/week had a lower risk of breast cancer in urban areas (OR=0.45, 95% CI=0.30-0.66, P<0.001 for trend), in the group 45-59 years old (OR=0.39, 95% CI=0.26-0.60, P<0.001 for trend), and in the group educated to senior high school or above (OR=0.39, 95% CI=0.25-0.59, P<0.001 for trend). There was an inverse association between the weekly frequency of dairy intake and the risk of ER+, PR+, and ER+PR+ breast cancer (all P<0.001 for trend). These results indicated that the weekly frequency of dairy intake was inversely associated with the risk of breast cancer among women in Northern and Eastern China.

Risk prediction for breast Cancer in Han Chinese women based on a cause-specific Hazard model.

BACKGROUND: Considering the lack of efficient breast cancer prediction models suitable for general population screening in China. We aimed to develop a risk prediction model to identify high-risk populations, to help with primary prevention of breast cancer among Han Chinese women. METHODS: A cause-specific competing risk model was used to develop the Han Chinese Breast Cancer Prediction model. Data from the Shandong Case-Control Study (328 cases and 656 controls) and Taixing Prospective Cohort Study (13,176 participants) were used to develop and validate the model. The expected/observed (E/O) ratio and C-statistic were calculated to evaluate calibration and discriminative accuracy of the model, respectively. RESULTS: Compared with the reference level, the relative risks (RRs) for highest level of number of abortions, age at first live birth, history of benign breast disease, body mass index (BMI), family history of breast cancer, and life satisfaction scores were 6.3, 3.6, 4.3, 1.9, 3.3, 2.4, respectively. The model showed good calibration and discriminatory accuracy with an E/O ratio of 1.03 and C-statistic of 0.64. CONCLUSIONS: We developed a risk prediction model including fertility status and relevant disease history, as well as other modifiable risk factors. The model demonstrated good calibration and discrimination ability.

Association of PTPN1 polymorphisms with breast cancer risk: A case-control study in Chinese females.

BACKGROUND: Breast cancer (BC) risk, development, and prognosis were closely related to obesity, diabetes mellitus, and metabolic syndrome. Protein tyrosine phosphatase, non-receptor type 1 (PTPN1) located on chromosome 20q13, could negatively regulate insulin and leptin signaling. In this study, we determined the association of PTPN1 polymorphisms with BC risk. METHODS: We analyzed the distribution of 11 selected PTPN1 single nucleotide polymorphisms in Chinese female patients with BC (n = 953) and healthy controls (n = 963) based on a multicenter case-control study. The association of PTPN1 genotypes and haplotypes frequencies with BC risk were determined by logistic regression analysis. Analyses were further stratified by body mass index (BMI), waist-hip rate (WHR), diabetes mellitus history, and fasting plasma glucose level. The eQTL (expression Quantitative Trait Loci) analysis for PTPN1 was conducted by GTEx database. RESULTS: There were significant differences between BC cases and control groups in menopausal status, number of births, and BMI. Four single nucleotide polymorphisms (SNPs; rs3215684, rs3787345, rs718049, and rs718050) decreased overall BC risk, and other seven SNPs showed no significant association with BC risk. In multivariate analysis, BMI and rs3215684 DT + DD genotype were identified as independent risk factors for BC, and mutated genotypes of rs3215684 were correlated with increased PTPN1 expression. There are no haplotypes showed different frequencies between cases and controls. In the stratified analysis, rs2206656 showed a significant association with decreased BC risk in the subgroup of BMI ≤ 24 kg/m 2 , while rs3215684 and rs718049 showed lower BC risk in the subgroup of WHR > 0.85. Seven SNPs showed lower BC risk in the subgroup with diabetes mellitus history and/or fasting plasma glucose level ≥ 7 mM, while rs754118 decreased BC risk in the subgroup of fasting plasma glucose level < 7 mM. CONCLUSION: Our findings suggest that PTPN1 SNPs associated with BC susceptibility in Chinese females, which also suggested a novel mechanism between obesity, diabetes mellitus, and BC risk.