VEGFA/NRP-1/GAPVD1 axis promotes progression and cancer stemness of triple-negative breast cancer by enhancing tumor cell-macrophage crosstalk.

Triple-negative breast cancer (TNBC) has long been considered a major clinical challenge due to its aggressive behavior and poor prognosis. Cancer stem cells (CSCs) are known as the main cells responsible for tumor origination, progression, recurrence and metastasis. Here, we report that M2-type tumor-associated macrophages (TAMs) contribute to cancer stemness in TNBC cells via the secretion of VEGFA. Reciprocally, elevated VEGFA expression by TAM-educated TNBC cells acts as a regulator of macrophage polarization, therefore constitute a feed-back loop between TNBC cells and TAMs. Mechanistically, VEGFA facilitates the CSC phenotype via the NRP-1 receptor and downstream GAPVD1/Wnt/ß-catenin signaling pathway in TNBC cells. Our study underscores the crosstalk between TNBC cells and TAMs mediated by VEGFA and further clarifies the role and underlying mechanisms of the VEGFA/NRP-1/GAPVD1 axis in regulating cancer stemness. We also document an immunosuppressive function of VEGFA in the tumor microenvironment (TME). Therefore, the present study indicates crosstalk between TNBC cells and TAMs induced by VEGFA and provides a potential implication for the combination of immunotherapy and VEGFA-targeted agents in TNBC therapy.

CYP4B1 polymorphisms and the risk of breast cancer in Chinese women: a case-control study.

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/m2 (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/m2, 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.

SMAD7 gene polymorphisms and their influence on patients with colorectal cancer.

Colorectal cancer (CRC) is a prevalent malignant tumor, and its pathogenesis is still not fully understood. Studies have shown that SMAD7 gene polymorphisms can affect CRC susceptibility, but the results have been inconsistent and require additional confirmation. Our study aimed to evaluate the effect of SMAD7 variants on the risk of CRC in the Chinese Han population. A total of five single nucleotide polymorphisms (SNPs) in SMAD7 were genotyped among 696 CRC patients and 696 healthy participants using the MassARRAY iPLEX platform. SNPs were evaluated for their associations with CRC using logistic regression analysis under multiple genetic models. The false-positive report probability (FPRP) analysis was used to validate the positive findings. Our study indicated that rs11874392 showed an increased association with CRC risk (odds ratio, 1.31; 95% confidence interval, 1.04-1.67; p = 0.024). Stratified analysis showed that rs11874392 might increase the risk of CRC in females (OR = 1.70, p = 0.028), individuals with smoking (OR = 1.87, p = 0.026), and drinking (OR = 1.38, p = 0.027). The rs11874392 was found to be related to an elevated risk of rectal cancer (OR = 1.73, p = 0.003), but not with colon cancer. FPRP analysis demonstrated that all of these associations were statistically significant (FPRP <0.2). Additionally, rs11874392 was the strongest predictive model for CRC. This study provides evidence that the SMAD7 rs11874392 is related to an increased susceptibility to CRC.

Impact of MIR31HG polymorphisms on risk of breast cancer in Chinese women.

BACKGROUND: Breast cancer (BC) is one of the leading causes of death worldwide. This study explored the relationship between the MIR31HG gene polymorphisms and the risk of BC in Chinese women. METHODS: Eight single nucleotide polymorphisms (SNPs) in MIR31HG were genotyped among 545 patients with BC and 530 healthy controls using Agena MassARRAY analysis. The PLINK software was used to calculate the odds ratio (OR) and 95% confidence intervals (CIs) via the logistic regression analysis. Multi-factor dimensionality reduction (MDR) analysis was performed to study the impact of SNP-SNP interaction on BC risk. RESULTS: MIR31HG rs72703442-AA (OR 0.29, 95% CI 0.10-0.79, p = 0.026), rs55683539-TT (OR 0.46, 95% CI 0.26-0.80, p = 0.012) and rs2181559-AA (OR 0.59, 95% CI 0.40-0.89, p = 0.038) were associated with a reduced risk of BC in Chinese women, as well as stratified results at age ≥ 52 years. Rs79988146 was correlated with estrogen receptor (ER) and progesterone receptor (PR)in Chinese female BC patients under various genetic models. Age at menarche stratification indicated that rs1332184 was associated with increased risk in BC patients, whereas stratification by number of births indicated that rs10965064 was associated with reduced risk in BC patients. MDR analysis showed that the best single-locus model for predicting of BC risk are rs55683539, which, rs55683539-CC group was a high risk group and rs55683539-TT group was a low risk group. CONCLUSIONS: The results indicated that the MIR31HG polymorphisms were associated with a reduced risk of BC in Chinese women.

Comprehensive Analysis of the Expression and Prognosis of chromobox Family Members in Breast Cancer.

BACKGROUND: Chromobox proteins are canonical components of the Polycomb group family and play pivotal roles in several cancers. However, little is known about the function, prognostic value and drug sensitivity of CBX family members in breast cancer. METHODS: In this study we investigated the expression, prognosis value and drug sensitivity of CBX family in breast cancer using the ONCOMINE, GEPIA, Human Protein Atlas and Kaplan-Meier Plotter databases, etc. and preliminary verified the expression of CBX family in breast cancer cell lines by RT-qPCR. RESULTS: We found that the expression levels of CBX1/2/3/4/8 members were elevated in breast cancer tissues compared to adjacent normal breast tissues, while the expression levels of CBX6/7 genes were reduced in breast cancer tissue. In vitro qRT-PCR validated the expression differences of CBX1/2/3/4/8 in breast cancer cell lines. Further analysis showed expression of CBX family members was remarkably correlated with cancer subgroups. As nodal metastasis status increased, the mRNA expression of CBX1/2/3/4/8 members tended to be higher, while CBX6/7 tended to be lower. The expression of CBX1/2/3 was higher in patients with TP53 mutation and CBX6/7 expression tended to be lower in patients with TP53 mutation groups. High transcription levels of CBX2/3 were significantly associated with shorter overall survival in breast cancer patients, while lower expression of CBX4/5/6/7 members was associated with unfavorable overall survival. Moreover, a high mutation rate of CBX gene members (43%) was observed in breast cancer patients, and genetic alterations in CBX genes was associated with poor prognosis. CONCLUSION: Taken together, our results indicated that CBX2/3/6/7/8 could be considered prognostic and therapeutic biomarkers of breast cancer and are worthy of further study.

Association of chromosome 2 open reading frame 71 in colorectal cancer susceptibility.

BACKGROUND: Colorectal cancer (CRC) is a serious threat to human physical and mental health. Due to the novelty of the open reading frame (ORF), ORF has shown a wide range of new genetic associations in cancer. The purpose of this study was to explore the association between the C2orf71 SNPs and CRC susceptibility. METHODS: We recruited 1419 participants to perform an association analysis between C2orf71 SNPs and CRC risk through SNPStats online solftware. Genotyping was completed by the AgenaMassARRAY. In addition, we used false-positive report probability analysis to detect whether the positive findings were noteworthy observations. We also used Haploview 4.2 software and SNPStats online software to conduct the haplotype analysis and analysis of linkage disequilibrium (LD). Finally, the interaction of SNP-SNP in CRC risk was evaluated by multi-factor dimensionality reduction (MDR). RESULTS: The overall analysis showed thatC2orf71-rs17744093, -rs10200693, and -rs13385188 were significantly associated with the CRC susceptibility. C2orf71-rs17744093 was associated with CRC risk under dominant model (OR = 1.25, p = 0.048). -rs10200693 was associated with CRC risk under allele (OR = 1.17, p = 0.041) and log-additive model (OR = 1.16, p = 0.045). -rs13385188 had significant association with CRC risk under multiple genetic models (allele: OR = 1.19, p = 0.023; log-additive: OR = 1.18, p = 0.026). Multiple stratified analyses showed that except for the three candidate SNPS mentioned above, -rs10166913 (age < 60 years and drinking) and -RS17007544 (< 60 years) were associated with increased CRC risk. CONCLUSION: C2orf71-rs17744093, -rs10200693, -rs10166913, -rs17007544, and -rs13385188 were associated with CRC susceptibility.

A yes-associated protein 1- Notch1 receptor positive feedback loop promotes breast cancer lung metastasis by attenuating the bone morphogenetic protein 4-SMAD family member 1/5 signaling.

The Notch1 (Notch1 receptor) and yes-associated protein 1 (YAP1) signaling can regulate breast cancer metastasis. This study aimed at investigating whether and how these two signal pathways crosstalk to promote breast cancer lung metastasis. Here, we show that YAP1 expression was positively correlated with Notch1 in breast cancer according to bioinformatics and experimental validation. Mechanistically, YAP1 with TEA domain transcription factors (TEADs) enhanced Jagged1(JAG1)-Notch1 signaling. Meanwhile, Notch1 promoted YAP1 stability in breast cancer cells by inhibiting the ß-TrCP-mediated degradation, thereby, forming a YAP1- JAG1/Notch1 positive feedback loop in breast cancer. Furthermore, YAP1 enhanced the mammosphere formation and stemness of MDA-MB-231 cells by attenuating the inhibition of the BMP4-SMAD1/5 signaling. In vivo, the YAP1- JAG1/Notch1 positive feedback loop promoted the lung colonization of MDA-MB-231 cells. Our data for the first time indicate that the YAP1-Notch1 positive feedback loop promotes lung metastasis of breast cancer by modulating self-renewal and inhibiting the BMP4-SMAD1/5 signaling.

A pan-cancer analysis of collagen VI family on prognosis, tumor microenvironment, and its potential therapeutic effect.

BACKGROUND: Collagen VI family (COL6A) is a major member of extracellular matrix protein. There is accumulating evidence that COL6A is involved in tumorigenesis and tumor progression. In this study, we performed a systematic analysis of COL6A in pan-cancer based on their molecular features and clinical significance. METHODS: Based on updated public databases, we integrated several bioinformatics analysis methods to investigate the expression levels of COL6A as well as the relationship between their expression and patient survival, immune subtypes, tumor microenvironment, stemness scores, drug sensitivity, and DNA methylation. RESULTS: The expression levels of COL6A members varied in different cancers, suggesting their expression was cancer-dependent. Among COL6A members, COL6A1/2/3 were predicted poor prognosis in specific cancers. Furthermore, COL6A1/2/3 expression levels revealed a clear correlation with immune subtypes, and COL6A1/2/3 were associated with tumor purity, that is, gene expression levels were generally higher in tumors with higher stromal scores and immune scores. COL6A1/2/3 had a significantly negative correlation with RNA stemness scores, and meanwhile they were also related to DNA stemness scores in different degrees. In addition, the expression of COL6A1/2/3 was significantly related to drug sensitivity of cancer cells. Finally, our study revealed that COL6A1/2/3 expression was mainly negatively correlated with gene methylation, and the methylation levels showed remarkable differences in various cancers. CONCLUSIONS: These findings highlight both the similarities and differences in the molecular characteristics of COL6A members in pan-cancer, and provide comprehensive insights for further investigation into the mechanism of COL6A.

PITPNA-AS1/miR-98-5p to Mediate the Cisplatin Resistance of Gastric Cancer.

Gastric cancer (GC) is the most deadly gastrointestinal malignancy with high incidence and mortality. Although, molecular mechanisms which drive gastric cancer progression are extensively investigated, the roles of long noncoding RNA (lncRNA) in gastric cancer growth and drug sensitivity remain unclear. Platinum is a mainstay to treat gastric cancer, and platinum resistance always leads to the local recurrence of gastric cancer. Therefore, it is important to identify biomarkers or therapeutic targets to sensitize gastric cancer to platinum. In this study, we employ noncoding RNA sequencing and found that lncRNA PITPNA-AS1 is overexpressed in gastric cancer tissues and associated with poor survival of gastric cancer patients. Kockdown of PITPNA-AS1 in gastric cancer cells significantly inhibited cell growth and triggered apoptotic cell death in gastric cancer cells. Also, cisplatin treatment could decrease PITPNA-AS1 levels in gastric cancer cells through inhibiting H3K27ac. Besides, PITPNA-AS1 is elevated in cisplatin-resistant gastric cancer cells and tissues, PITPNA-AS1 knockdown could sensitize gastric cancer cells to cisplatin treatment. Furthermore, we identified that PITPNA-AS1 directly interacts and inhibits miR-98-5p. Therefore, PITPNA-AS1 could be served as a potential biomarkers and curative therapeutic targets for gastric cancer progression.

A bioinformatics analysis of zinc finger protein family reveals potential oncogenic biomarkers in breast cancer.

BACKGROUND: Zinc finger protein family is the largest transcription factor family in the human genome. Studies have shown that the aberrant expression of zinc finger protein (ZNF) had a potential role in tumorigenesis. However, due to the high complexity of the ZNF family genes, the role of the ZNF family genes in breast cancer (BRCA) is still lacking in systematic understanding. AIM: In the study, we aim to understand the expression profile, prognostic value, immune invasion pattern, tumor microenvironment, epigenetic and pathway relationships, and drug sensitivity of ZNFs using multi-omics data from public databases. RESULTS: We focused on six members of ZNFs, which were upregulated in a variety of cancers. Notably, ZNF750 and ZNF224 were lower expressed in BRCA, and their expressions were significantly associated with BRCA prognosis. We confirmed the observations obtained by analyzing the clinic-pathological data. Otherwise, the expressions of ZNFs were significantly related to stromal and immune scores, and was significantly different among different immune subtypes in BRCA. Here, we found down-regulated methylation of ZNF217 and ZNF750. The relationship between methylation and survival showed the survival was worse for hypo-methylation of ZNF750 in BRCA, which is consistent with the correlation of high expression of ZNF750 in BRCA with worse survival. CONCLUSIONS: Collectively, our results provide clues for a better understanding of the characterization of ZNF family genes in BRCA from a multi-omics perspective and show their potential for use as new tumor markers and therapeutic targets.

OTUD5-mediated deubiquitination of YAP in macrophage promotes M2 phenotype polarization and favors triple-negative breast cancer progression.

Macrophages, which are highly plastic, can be polarized to M1 or M2 subtypes according to the diverse signals in complex microenvironment. Studies have shown the activation of YAP, an oncogenic transcriptional co-activator, increased macrophage recruitment. However, its role in macrophage polarization remains to be elucidated, especially in triple-negative breast cancer (TNBC) progression. Here we found TNBC cells increased YAP expression in macrophages, which depended on OTUD5-mediated deubiquitination and stabilization of YAP, then the high expression of YAP polarized macrophage to the M2-like phenotype. Moreover, the elevation of YAP in M2-like macrophage promotes the pro-metastatic potential of TNBC cells via MCP-1/CCR2 pathway. We also observed high expression of YAP in M2 macrophage was negatively related to survival. Collectively, our finding suggested the therapeutic strategy that targets YAP+ M2 macrophage could be a novel option for TNBC treatment.

Establishment and validation of a prediction model for the probability of malignancy in solid solitary pulmonary nodules in northwest China.

BACKGROUND AND OBJECTIVES: To construct a prediction model of solitary pulmonary nodules (SPNs), to predict the possibility of malignant SPNs in patients aged 15-85 years in northwest China for clinical diagnostic and therapeutic decision-making. METHODS: The features of SPNs were assessed by multivariate logistic regression, followed by visualization using a nomogram. Hosmer lemeshow was applied to evaluate the fitting degree of the model. The area under the receiver operating characteristic (ROC) curve was identified to determine the discriminative ability of the model. RESULTS: Lobulation, spiculation, pleural-tag, carcinoembryonic antigen, neuron-specific enolase, and total serum protein were independent predictors of malignant pulmonary nodules (p < .05). Lobulation (100 points) scored the highest in the nomogram, and the Hosmer-Lemeshow goodness-of-fit statistic was 0.805 (p > .05). The area under curve (AUC) of the modeling and validation groups using logistic regression were 0.859 (95% CI, 0.805-0.903) and 0.823 (95% CI, 0.738-0.890), respectively. Moreover, the AUC of our model was higher than that of the Mayo model, VA model, and Peking University (AUC 0.823 vs. 0.655 vs. 0.603 vs. 0.521). CONCLUSION: Our prediction model is more suitable for predicting the possibility of malignant SPNs in northwest China, and can be calculated using a nomogram to determine further treatments.

An ALK-positive lung adenocarcinoma with gastric and skin metastasis: a case report and literature review.

Primary lung cancer with gastric metastasis is rare to see in the world, little is known about its characteristics. Here, we describe the first case of primary lung adenocarcinoma with gastric and skin metastases along with a review of literature to help clinical decision making. A 49-year-old woman admitted to our department for abdominal distension. The immunohistochemistry staining for the biopsy in the gastric fundus, back and lung showed positive for CK5/6, TTF-1, Napsin A and CK7, but negative for CK20, which strongly indicated all of them were homologous and might originate from lung adenocarcinoma. Chromosome mutation analysis presented an EML4-ALK fusion gene. Brain metastases occurred after 6 months with crizotinib treatment. More than two months later, intracranial lesions became more and larger as she persisted in taking crizotinib plus whole-brain radiotherapy (WBRT). Hence, alectinib was performed due to the continuous growth of brain lesions. When reexamined three months later, the craniocerebral lesions were significantly reduced and all tumor markers were up to normal level. This review comprised 42 published case reports in total. Generally, the average morbidity age was 62 years old, and male with smoking history were more prone to it. It could be found that squamous cell carcinoma (17/38) accounts for a high proportion of gastrointestinal metastases pathology, most of which were poorly differentiated. Surgical excision of the lesions was supposed to improve long-term prognosis, mitigate associated complications, decrease patients' pain, and enhance the quality of life. Gastric metastasis of lung cancer is apt to metastasize to the brain, and the prognosis is inferior. Crizotinib with preventive WBRT may be the optimal choice for NSCLC patients harboring ALK mutation in the initial treatment of gastric metastasis. However, If the lesion in the brain keep on going, timely replacement to alectinib is an appropriate choice.

Corrigendum: Myeloid-Derived Suppressor Cells Recruited by Chemokine (C-C Motif) Ligand 3 Promote the Progression of Breast Cancer via Phosphoinositide 3-Kinase-Protein Kinase B-Mammalian Target of Rapamycin Signaling.

[This corrects the article on p. 141 in vol. 23, PMID: 32395374.].

Human CD133-positive hematopoietic progenitor cells enhance the malignancy of breast cancer cells.

BACKGROUND: Human CD133+ hematopoietic progenitor cells (HPCs) are a specific subset of cells that can regulate tumor malignancy. However, the mechanism by which CD133+ HPCs affect the malignancy of human breast cancer has not been reported. METHODS: CD133+ HPCs were isolated and purified from human umbilical cord blood (UCB). We used in vitro culture of MCF-7 and MDA-MB-231 cell lines, and MCF-7 and MDA-MB-231 cells in nude mice to evaluate whether CD133+ HPCs affected the apoptosis, proliferation, invasion and epithelial mesenchymal transition EMT of breast cancer cells. RESULTS: Co-culture with CD133+ HPCs, but not UCB CD133- cells, promoted the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells, accompanied by reducing in vitro spontaneous apoptosis. Co-administration of these two lines with CD133+ HPCs significantly enhanced the growth of implanted breast cancer in vivo. Furthermore, co-culture with CD133+ HPCs, enhanced the invasion of breast cancer cells, N-cadherin and Vimentin expression, but reduced E-cadherin expression in breast cancer cells. CONCLUSIONS: Our study demonstrated that CD133+ HPCs enhance the malignancy of breast cancer cells by attenuating spontaneous apoptosis and promoting the process of epithelial mesenchymal transition. These findings may provide new insights into the role of human CD133+ HPCs in breast cancer pathogenesis. Therefore, CD133+ HPCs may be a new therapeutic target for inhibiting the progression of breast cancer.

IL-7R gene variants are associated with breast cancer susceptibility in Chinese Han women.

BACKGROUND: Interleukin 7 receptor (IL-7R) is a member of the type I cytokine receptor family, which affects the occurrence of various tumors by forming a signaling complex with its ligand Interleukin 7 (IL-7). This study aimed to explore the potential relationships of IL-7R polymorphisms with breast cancer susceptibility in the Chinese Han women. METHODS: Five polymorphisms of IL-7R gene (rs969129, rs10213865, rs10053847, rs118137916, and rs6451231) form 553 patients and 550 healthy individuals among the Chinese Han women were genotyped using Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to evaluate the relationship. RESULTS: The resulted of this study showed that rs10213865 was related to an increased breast cancer risk in allele (P = 0.045), dominant (P = 0.040), and log-additive (P = 0.029) models. As for rs969129, an increased risk of breast cancer was found in the allele (P = 0.018), co-dominant (P = 0.017), recessive (P = 0.034), and additive (P = 0.019) models. Rs6451231 was related to an increased risk of breast cancer under allele (P = 0.018), co-dominant (P = 0.021), and log-additive (P = 0.019) models. Age stratified analysis revealed that rs6451231 could enhance risk of breast cancer among the individuals older than 52 years. Furthermore, there was a significant correlation between haplotype Crs969129Grs10213865Ars10053847Grs118137916 and the decreased risk of breast cancer (P = 0.010). CONCLUSIONS: This study firstly proved that IL-7R polymorphisms were significantly correlated with an increased susceptibility of breast cancer in the Chinese Han women.

Metformin suppresses HIF-1α expression in cancer-associated fibroblasts to prevent tumor-stromal cross talk in breast cancer.

The tumor microenvironment (TME) is a crucial factor in cancer progression. In breast cancer, cancer-associated fibroblasts (CAFs) and the derived stromal components have been recognized as comprising the majority of the pathological structure of the TME. In this study, we show that metformin (Met), a diabetes drug, transforms CAFs in the TME. Met disrupts tumor-stromal cross talk by preventing breast cancer cell transforming growth factor-ß (TGF-ß) signaling and the production of stromal-derived factor-1 (SDF-1) and interleukin-8 (IL-8) by CAFs. The suppression of bidirectional signaling between tumor cells and CAFs by Met is attributed to increased phospho-AMP kinase (p-AMPK) levels. By upregulating p-AMPK in CAFs, Met induces prolyl hydroxylases (PHDs), leading to the degradation of hypoxia-inducible factor-1α (HIF-1α) in CAFs. Moreover, interruption of HIF-1α-driven SDF-1 signaling in CAFs by Met leads to decreased breast cancer cell invasion. These findings suggest that Met may be used to target tumor-promoting signaling between CAFs and breast cancer cells in the TME.

Impact of NR5A2 and RYR2 3'UTR polymorphisms on the risk of breast cancer in a Chinese Han population.

OBJECTIVES: The NR5A2 and RYR2 genes are important players in steroid metabolism and play an important role in cancer research. In this research, we want to evaluate the effect of NR5A2 and RYR2 polymorphisms on breast cancer (BC). METHODS: Four single nucleotide polymorphisms on NR5A2 and RYR2 were selected to genotype by Agena MassARRAY in 379 BC patients and 407 healthy controls. Using the PLINK software to calculate the Odds ratio (OR) and 95% confidence intervals (CIs) via the logistic regression analysis to evaluate the risk for BC. RESULTS: We found that NR5A2 rs2246209 significantly decreased the risk of BC with the AA genotype (OR 0.58, 95%CI 0.34-0.99, p = 0.049), and recessive model (OR 0.59, 95%CI 0.35-0.99, p = 0.046); rs12594 in the RYR2 gene significantly decreased the risk of BC in the GG genotype (OR 0.44, 95%CI 0.22-0.88, p = 0.020), and recessive model (OR 0.43, 95%CI 0.21-0.85, p = 0.016). Further stratification analysis showed that NR5A2 rs2246209 was related to a lower incidence of BC affected by age, lymph nodes metastasis, and tumor stage; RYR2 rs12594 was related to a decreased BC risk restricted by age, estrogen receptor (ER), progesterone receptor (PR), menopausal status, tumor size, and tumor stage. Rs12594 in the RyR2 gene remained significant on the genetic susceptibility of PR-positive BC after Bonferroni correction (p < 0.0125). CONCLUSIONS: This study provides an evidence that NR5A2 rs2246209 and RYR2 rs12594 decreased the risk of breast cancer.

Myeloid-Derived Suppressor Cells Recruited by Chemokine (C-C Motif) Ligand 3 Promote the Progression of Breast Cancer via Phosphoinositide 3-Kinase-Protein Kinase B-Mammalian Target of Rapamycin Signaling.

PURPOSE: Numerous studies have shown that the frequency of myeloid-derived suppressor cells (MDSCs) is associated with tumor progression, metastasis, and recurrence. Chemokine (C-C motif) ligand 3 (CCL3) may be secreted by tumor cells and attract MDSCs into the tumor microenvironment. In the present study, we aimed to explore the molecular mechanisms whereby CCL3 is involved in the interaction of breast cancer cells and MDSCs. METHODS: The expression of CCL3 and its receptors was investigated using real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The cell counting Kit-8, wound healing, and transwell assays were performed to study cell growth, migration, and invasion. Cell cycling, apoptosis, and the frequency of MDSCs were investigated through flow cytometry. Transwell assays were used for co-culture and chemotaxis detection. Markers of the epithelial-mesenchymal transition (EMT) were determined with western blotting. The role of CCL3 in vivo was studied via tumor xenograft experiments. RESULTS: CCL3 promoted cell proliferation, migration, invasion, and cycling, and inhibited apoptosis of breast cancer cells in vitro. Blocking CCL3 in vivo inhibited tumor growth and metastases. The frequency of MDSCs in patients with breast cancer was higher than that in healthy donors. Additionally, MDSCs might be recruited by CCL3. Co-culture with MDSCs activated the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway and promoted the EMT in breast cancer cells, and their proliferation, migration, and invasion significantly increased. These changes were not observed when breast cancer cells with CCL3 knockdown were co-cultured with MDSCs. CONCLUSION: CCL3 promoted the growth of breast cancer cells, and MDSCs recruited by CCL3 interacted with these cells and then activated the PI3K-Akt-mTOR pathway, which led to EMT and promoted the migration and invasion of the cells.

The effect of interleukin 10 polymorphisms on breast cancer susceptibility in Han women in Shaanxi Province.

BACKGROUND: Previous studies have reported on several genetic variants related to breast cancer, but a substantial proportion of mutation loci have not yet been identified. In the current study, we aimed to evaluate the association between single nucleotide polymorphisms (SNPs) of interleukin-10 (IL-10) and susceptibility to breast cancer in Shaanxi Han women in China. METHODS: Six SNPs were genotyped in 530 breast cancer patients and 628 healthy women from the First Affiliated Hospital of Xi'an Jiaotong University Hospital. Odds ratios and 95% confidence intervals were calculated by unconditional logistic regression analysis to assess the association between breast cancer risk and polymorphisms of six loci. RESULTS: Two SNPs, rs3024490 and rs1800871, were found to be significantly different between breast cancer patients and healthy women. These SNPs also increased the risk of breast cancer in co-dominant and dominant models. Moreover, another SNP, rs1554286, was significantly associated with an increased risk of breast cancer in the co-dominant model. Functional assessments indicated that these three variants may influence the expression and transcription factor binding of IL-10. CONCLUSIONS: Our findings suggest that variants of IL-10 may be likelihood risk factors for the development and progression of breast cancer. Future studies should replicate this study and evaluate functional assessments in Chinese Han women and women from other regions.