G6PD activation in TNBC cells induces macrophage recruitment and M2 polarization to promote tumor progression.

Glucose-6-phosphate dehydrogenase (G6PD) is involved in triple-negative breast cancer (TNBC) progression. Metabolic crosstalk between cancer cells and tumor-associated macrophages mediates tumor progression in TNBC. Molecular biological methods were applied to clarify the mechanism of the crosstalk between TNBC cells and M2 macrophages. In the present study, we verified that G6PD overexpression drives M2 macrophage polarization by directly combining with phospho-STAT1 and upregulating CCL2 and TGF-ß1 secretion in TNBC cells. In turn, M2-like TAMs activated TNBC cells through IL-10 secretion, providing feedback to upregulate G6PD and promote TNBC cell migration and proliferation in vitro. Furthermore, we found that 6-AN (a specific inhibitor of G6PD) not only suppressed the cancer-driven polarization of macrophages toward the M2 phenotype but also inhibited the inherent M2 polarization of macrophages. Targeting the G6PD-regulated pentose phosphate pathway restrained TNBC progression and M2-type polarization of macrophages in vitro and in vivo.

Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) accounts for 85~90% of lung cancer cases, with a poor prognosis and a low 5-year survival rate. Sphingosine kinase-1 (SPHK1), a key enzyme in regulating sphingolipid metabolism, has been reported to be involved in the development of NSCLC, although the underlying mechanism remains unclear. In the present study, we demonstrated the abnormal signature of SPHK1 in NSCLC lesions and cell lines of lung cancers with a potential tumorigenic role in cell cycle regulation. Functionally, ectopic Pre-B cell leukemia homeobox-1 (PBX1) was capable of restoring the arrested G1 phase induced by SPHK1 knockdown. However, exogenous sphingosine-1-phosphate (S1P) supply had little impact on the cell cycle arrest by PBX1 silence. Furthermore, S1P receptor S1PR3 was revealed as a specific switch to transport the extracellular S1P signal into cells, and subsequently activated PBX1 to regulate cell cycle progression. In addition, Akt signaling partially participated in the SPHK1/S1PR3/PBX1 axis to regulate the cell cycle, and the Akt inhibitor significantly decreased PBX1 expression and induced G1 arrest. Targeting SPHK1 with PF-543 significantly inhibited the cell cycle and tumor growth in preclinical xenograft tumor models of NSCLC. Taken together, our findings exhibit the vital role of the SPHK1/S1PR3/PBX1 axis in regulating the cell cycle of NSCLC, and targeting SPHK1 may develop a therapeutic effect in tumor treatment.

A case-control study about the association between vascular endothelial growth inhibitor gene polymorphisms and breast cancer risk in female patients in Northeast China.

OBJECTIVE: The inhibition of the neovascularization in tumors is a potential therapeutic target of cancer. Vascular endothelial growth inhibitor (VEGI) is a member of the TNF superfamily which has the ability to suppress the formation of new vessels in tumors. In order to study the association between VEGI gene polymorphisms and breast cancer risk, a case-control study was conducted in Chinese Han women in Northeast China. METHODS: Our study involved 708 female breast cancer patients and 685 healthy volunteers. Four SNPs of VEGI gene were analyzed through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between VEGI gene polymorphisms and breast cancer risk was analyzed in our study. The relation between VEGI gene variants and clinical features of breast cancer including lymph node (LN) metastasis, estrogen receptor (ER), progestrogen receptor (PR), tumor protein 53 (p53), human epidermal growth factor receptor 2 (Her-2) and triple negative (ER-/PR-/Her-2-) status was analyzed as well. RESULTS: We found that the CT genotype and T allele of rs6478106 were more frequent in patients than in controls. There was also a statistical difference in the distribution of Crs6478106Grs4263839 haplotype between patients and controls. In addition, SNP rs6478106 and rs4979462 were related with the Her-2 status. CONCLUSIONS: Our results suggest that VEGI gene variants may be related to the breast cancer risk and the clinical features of breast cancer in Chinese Han women in Northeast China.

Co-stimulators CD40-CD40L, a potential immune-therapy target for atherosclerosis: A review.

The interaction between CD40 and CD40 ligand (CD40L) a crucial co-stimulatory signal for activating adaptive immune cells, has a noteworthy role in atherosclerosis. It is well-known that atherosclerosis is linked to immune inflammation in blood vessels. In atherosclerotic lesions, there is a multitude of proinflammatory cytokines, adhesion molecules, and collagen, as well as smooth muscle cells, macrophages, and T lymphocytes, particularly the binding of CD40 and CD40L. Therefore, research on inhibiting the CD40-CD40L system to prevent atherosclerosis has been ongoing for more than 30 years. However, it's essential to note that long-term direct suppression of CD40 or CD40L could potentially result in immunosuppression, emphasizing the critical role of the CD40-CD40L system in atherosclerosis. Thus, specifically targeting the CD40-CD40L interaction on particular cell types or their downstream signaling pathways may be a robust strategy for mitigating atherosclerosis, reducing potential side effects. This review aims to summarize the potential utility of the CD40-CD40L system as a viable therapeutic target for atherosclerosis.

MCL restrained ROS/AKT/ASAH1 pathway to therapy tamoxifen resistance breast cancer by stabilizing NRF2.

Tamoxifen resistance is a common and difficult problem in the clinical treatment of breast cancer (BC). As a novel antitumor agent, Micheliolide (MCL) has shown a better therapeutic effect on tumours; however, little is known about MCL and its role in BC therapy. With tamoxifen stimulation, drug-resistant BC cells MCF7TAMR and T47DTAMR obtained a high oxidative status and Amidohydrolase 1 (ASAH1) was abnormally activated. The inhibition of ASAH1 rescued the sensitivity of resistant cells to tamoxifen. We found that MCL inhibited the expression of ASAH1 and cell proliferation, especially in MCF7TAMR and T47DTAMR cells. The high oxidative stress status of resistant cells stimulated the expression of ASAH1 by positively regulating AKT, which was restrained by MCL. MCL activated NRF2 by directly binding to KEAP1 and promoting the antioxidant level of tamoxifen-resistant (TAMR) cells. In addition, ACT001, the prodrug of MCL, significantly inhibited the tumour growth of TAMR cells in preclinical xenograft tumour models. In conclusion, ASAH1 mediates tamoxifen resistance in ER-positive BC cells. MCL could activate the cellular antioxidant system via NRF2/KEAP1 and inhibit ASAH1 expression through the ROS/AKT signalling pathway, thus suppressing cell proliferation. MCL could be used as a potential treatment for TAMR-BC.

Targeting estrogen mediated CYP4F2/CYP4F11-20-HETE metabolic disorder decelerates tumorigenesis in ER+ breast cancer.

Purpose: As the most common subset of breast cancer (BC), estrogen receptor positive (ER+) BC accounting for 80% of cases, has become a global public health concern. The female hormone estrogen (E2) unequivocally drives ER + breast malignancies. The reasons that estrogen affects BC development has long been considered, yet further study remains to be conducted of the molecular events in the E2-estrogen receptor α (ERα) signaling pathway in ER + BC progression, especially lipid metabolism, so providing more options for tailored and individualized therapy. Our aim is to find out new targets and clinical biomarkers for ER + breast cancer treatment from the perspective of lipid metabolism. Methods: Lipid metabolomics profiling was used to examine the membrane phospholipid stimulated by E2. Clinical BC samples were used to assess the association of CYP4F2, CYP4F11 expression with clinicopathological characteristics and patient outcomes. Some inhibitors of main enzymes in AA metabolism were used combined with E2 to assess roles of CYP4F2/CYP4F11 in the progression of ER + BC. CYP4F2, CYP4F11 overexpression and knockdown BC cell lines were employed to examine the effects of CYP4F2, CYP4F11 on cellular proliferation, apoptosis and tumor growth. Western blotting, qPCR, Immunohistochemical staining and flow cytometry were also conducted to determine the underlying mechanisms related to CYP4F2, CYP4F11 function. Results: The activation of the CYP450 signaling pathway in arachidonic acid metabolism contributed to ER + BC tumorigenesis. In ER + BC, CYP4F2 and CYP4F11 overexpression induced by E2 could promote cancer cell proliferation and resistance to apoptosis by producing the metabolite 20-HETE and activating the antiapoptotic protein Bcl-2. CYP4F2 and CYP4F11 elevation correlates with poorer overall survival and disease-free survival in ER + BC patients. Conclusion: CYP4F2, CYP4F11 and their metabolite 20-HETE could serve as effective prognostic markers and attractive therapeutic targets for novel anticancer drug development about ER + BC.

Inhibition of Polo-like kinase 1 (PLK1) triggers cell apoptosis via ROS-caused mitochondrial dysfunction in colorectal carcinoma.

BACKGROUND: Colorectal cancer (CRC) is one of the most frequently diagnosed cancers. Polo-like kinase 1 (PLK1), a member of the serine/threonine kinase PLK family, is the most investigated and essential in the regulation of cell cycle progression, including chromosome segregation, centrosome maturation and cytokinesis. However, the nonmitotic role of PLK1 in CRC is poorly understood. In this study, we explored the tumorigenic effects of PLK1 and its potential as a therapeutic target in CRC. METHODS: GEPIA database and immunohistochemistry analysis were performed to evaluate the abnormal expression of PLK1 in CRC patients. MTT assay, colony formation and transwell assay were performed to assess cell viability, colony formation ability and migration ability after inhibiting PLK1 by RNAi or the small molecule inhibitor BI6727. Cell apoptosis, mitochondrial membrane potential (MMP) and ROS levels were evaluated by flow cytometry. Bioluminescence imaging was performed to evaluate the impact of PLK1 on CRC cell survival in a preclinical model. Finally, xenograft tumor model was established to study the effect of PLK1 inhibition on tumor growth. RESULTS: First, immunohistochemistry analysis revealed the significant accumulation of PLK1 in patient-derived CRC tissues compared with adjacent healthy tissues. Furthermore, PLK1 inhibition genetically or pharmacologically significantly reduced cell viability, migration and colony formation, and triggered apoptosis of CRC cells. Additionally, we found that PLK1 inhibition elevated cellular reactive oxygen species (ROS) accumulation and decreased the Bcl2/Bax ratio, which led to mitochondrial dysfunction and the release of Cytochrome c, a key process in initiating cell apoptosis. CONCLUSION: These data provide new insights into the pathogenesis of CRC and support the potential value of PLK1 as an appealing target for CRC treatment. Overall, the underlying mechanism of inhibiting PLK1-induced apoptosis indicates that the PLK1 inhibitor BI6727 may be a novel potential therapeutic strategy in the treatment of CRC.

Targeting glucose-6-phosphate dehydrogenase by 6-AN induces ROS-mediated autophagic cell death in breast cancer.

Dysregulation of G6PD involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. The PPP plays a pivotal role in meeting the anabolic demands of cancer cells. However, the detailed underlying molecular mechanisms of targeting the G6PD-regulated PPP in breast cancer remain unclear. In this study, we aimed to elucidate the molecular pathways mediating the effects of G6PD on cancer progression. Clinical sample analysis found that the expression of G6PD in breast cancer patients was higher than that in normal controls, and patients with higher G6PD expression had poor survival. Gene knockdown or inhibition of G6PD by 6-AN in MCF-7 and MDA-MB-231 cells significantly decreased cell viability, migration, and colony formation ability. G6PD enzyme activity was inhibited by 6-AN treatment, which caused a transient upregulation of ROS. The elevated ROS was independent of cell apoptosis and thus associated with abnormal activated autophagy. Accumulated ROS levels induced autophagic cell death in breast cancer. Inhibition of G6PD suppresses tumour growth in preclinical models of breast cancer. Our results indicate that targeting the G6PD-regulated PPP could restrain tumours in vitro and in vivo, inhibiting G6PD caused cell death by over-activating autophagy, therefore leading to inhibited proliferation and tumour formation.

Association of CD27 and CD70 gene polymorphisms with risk of sporadic breast cancer in Chinese women in Heilongjiang Province.

CD27 and its ligand, CD70, are major costimulatory molecules whose interaction can regulate the expansion and differentiation of effector and memory T-cell populations. Their abnormal expression can disturb the immune response and lead to an increased risk of cancer. This study aims to evaluate the associations between single nucleotide polymorphisms (SNPs) in CD27/CD70 gene and breast cancer susceptibility. Five tagSNPs and one coding polymorphism in CD27, as well as three tagSNPs in CD70, were genotyped in a case-control study of 610 breast cancer patients and 617 healthy controls. In CD27, rs3136550 CT and rs2267966 AT genotypes were associated with a decreased risk of breast cancer (P = 0.03, OR = 0.76; P = 0.02, OR = 0.75, respectively). In CD70, AG and GG genotypes in rs1862511 and CC genotype in rs2059154 also showed significant associations with a decreased risk of breast cancer (P = 2.00 × 10(-3), OR = 0.69; P = 0.03, OR = 0.62; P = 2.00 × 10(-3), OR = 0.53; respectively). Significant associations were also found in the dominant and recessive models for rs2059154 and dominant model for rs1862511. In haplotype analysis, CCGAG haplotype in CD27 and TAA haplotype in CD70 conferred an increased risk of breast cancer (P = 5.60 × 10(-3); P = 7.75 × 10(-5), respectively), but TGC, TAC and TGA haplotypes in CD70 were associated with a decreased risk of breast cancer (P = 0.01; P = 5.2 × 10(-3); P = 2.00 × 10(-3), respectively). The associations of CCGAG, TAA, TAC and TGA haplotypes remained significant after correcting P value for multiple testing. Significant associations were shown between the SNPs of CD27 and lymph node metastasis, and ER and PR statuses. These results indicate that CD27 and CD70 gene polymorphisms may affect the risk of breast cancer and show that some SNPs are associated with breast cancer characteristics in a northern Chinese population.

Association of CTLA-4 gene polymorphisms with sporadic breast cancer risk and clinical features in Han women of northeast China.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule that plays a pivotal role in downregulating T-cell mediated immune responses. To determine the role of CTLA-4 in tumor immunity, and to validate previous results as well, we investigated four tag single nucleotide polymorphisms (SNPs) of CTLA-4 in a relatively large Chinese Han cohort from northeastern China. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 581 patients and 566 age-matched controls. Our data indicated that compared with the common genotype and allele of each SNP, the -1722 CC genotype and C allele showed an increased risk of breast cancer (P = 0.030, odds ratio (OR) = 1.457, 95% confidence internal (CI) 1.036-2.051; P = 0.024, OR = 1.214, 95% CI 1.026-1.436, respectively). The -1661 GG genotype and G allele were also associated with an increased risk of breast cancer (P = 0.018, OR = 1.396, 95% CI 1.058-1.843; P = 0.013, OR = 1.353, 95% CI 1.066-1.717, respectively). In the haplotype analysis, the CAAA haplotype showed a higher frequency in cases (P = 0.004), and this association remained significant after correcting the P value for multiple testing. Associations were shown between the SNPs of CTLA-4 and lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR) and P53 statuses. These results indicate that some SNPs in the CTLA-4 gene may affect the risk of breast cancer and show that some SNPs are associated with breast cancer characteristics in Han women in northeastern China.

Cardiac Toxicity From Adjuvant Targeting Treatment for Breast Cancer Post-Surgery.

Breast cancer is one of the most prevalent types of cancers worldwide, especially for females. Surgery is the preferred treatment for breast cancer, and various postoperative adjuvant therapies can be reasonably used according to different pathological characteristics, especially traditional radiotherapy, chemotherapy, and endocrine therapy. In recent years, targeting agent therapy has also become one of the selective breast cancer treatment strategies, including anti-HER-2 drugs, CDK4/6 inhibitor, poly ADP-ribose polymerase inhibitor, PI3K/AKT/mTOR pathway inhibitor, ER targeting drugs, and aromatase inhibitor. Because of the different pathologic mechanisms of these adjuvant therapies, each of the strategies may cause cardiotoxicity in clinic. The cardiac adverse events of traditional endocrine therapy, radiotherapy, and chemotherapy for breast cancer have been widely detected in clinic; however, the targeting therapy agents have been paid more attention with the extension of application. This review will summarize the cardiac toxicity of various adjuvant therapies for breast cancer, especially for targeting drug therapy.

Costimulatory and coinhibitory molecules of B7-CD28 family in cardiovascular atherosclerosis: A review.

Accumulating evidence supports the active involvement of vascular inflammation in atherosclerosis pathogenesis. Vascular inflammatory events within atherosclerotic plaques are predominated by innate antigen-presenting cells (APCs), including dendritic cells, macrophages, and adaptive immune cells such as T lymphocytes. The interaction between APCs and T cells is essential for the initiation and progression of vascular inflammation during atherosclerosis formation. B7-CD28 family members that provide either costimulatory or coinhibitory signals to T cells are important mediators of the cross-talk between APCs and T cells. The balance of different functional members of the B7-CD28 family shapes T cell responses during inflammation. Recent studies from both mouse and preclinical models have shown that targeting costimulatory molecules on APCs and T cells may be effective in treating vascular inflammatory diseases, especially atherosclerosis. In this review, we summarize recent advances in understanding how APC and T cells are involved in the pathogenesis of atherosclerosis by focusing on B7-CD28 family members and provide insight into the immunotherapeutic potential of targeting B7-CD28 family members in atherosclerosis.

Pyrotinib Targeted EGFR-STAT3/CD24 Loop-Mediated Cell Viability in TSC.

Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor, designed for the therapy of HER2-positive breast cancers. Inhibition of the epidermal growth factor receptor (EGFR, HER family) efficiently and selectively suppresses the proliferation of human TSC2-deficient smooth muscle cells and reverses lung changes in LAM/TSC. Our pilot study indicated that pyrotinib dramatically restrained the vitality of TSC2-deficient cells compared to its limited impact on TSC2-expression cells. Pyrotinib induced G1-phase arrest and triggered apoptosis by blocking abnormally activated CD24 in TSC2-deficient cells. CD24 is not only an important immune checkpoint, but is also involved in the regulation of signaling pathways. Pyrotinib inhibited the nuclear import of pEGFR and restrained the pEGFR/pSTAT3 signals, which directly boosted the transcriptional expression of CD24 by binding to its promoter region. In reverse, CD24 enhanced pEGFR function by directly binding. Pyrotinib specifically targeted TSC2-deficient cells, inhibited tumor cell viability and induced apoptosis through EGFR-STAT3/CD24 Loop in vivo and in vitro. Thus, pyrotinib may be a promising new therapeutic drug for TSC treatment.

Targeting SPHK1/S1PR3-regulated S-1-P metabolic disorder triggers autophagic cell death in pulmonary lymphangiomyomatosis (LAM).

Lymphangioleiomyomatosis (LAM), a progressive pulmonary disease exclusively affecting females, is caused by defects or mutations in the coding gene tuberous sclerosis complex 1 (TSC1) or TSC2, causing the mammalian target of rapamycin complex 1 (mTORC1) activation and autophagy inhibition. Clinically, rapamycin shows limited cytocidal effects, and LAM recurs after drug withdrawal. In this study, we demonstrated that TSC2 negatively regulated the sphingolipid metabolism pathway and the expressions of sphingosine kinase 1 (SPHK1) and sphingosine-1-phosphate receptor 3 (S1PR3) were significantly elevated in LAM patient-derived TSC2-deficient cells compared to TSC2-addback cells, insensitive to rapamycin treatment and estrogen stimulation. Knockdown of SPHK1 showed reduced viability, migration and invasion in TSC2-deficient cells. Selective SPHK1 antagonist PF543 potently suppressed the viability of TSC2-deficient cells and induced autophagy-mediated cell death. Meanwhile, the cognate receptor S1PR3 was identified to mediating the tumorigenic effects of sphingosine-1-phosphate (S1P). Treatment with TY52156, a selective antagonist for S1PR3, or genetic silencing using S1PR3-siRNA suppressed the viability of TSC2-deficient cells. Both SPHK1 and S1PR3 inhibitors markedly exhibited antitumor effect in a xenograft model of TSC2-null cells, restored autophagy level, and triggered cell death. Together, we identified novel rapamycin-insensitive sphingosine metabolic signatures in TSC2-null LAM cells. Therapeutic targeting of aberrant SPHK1/S1P/S1PR3 signaling may have potent therapeutic benefit for patients with TSC/LAM or other hyperactive mTOR neoplasms with autophagy inhibition.

Evidence on the association between NQO1 Pro187Ser polymorphism and breast cancer risk in the current studies: a meta-analysis.

Several molecular epidemiological studies were conducted in recent years to evaluate the association between NQO1 Pro187Ser polymorphism and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis on 3177 cases with breast cancer and 4038 controls from seven published case-control studies showed that the 187Ser allele was not associated with a significantly increased risk of breast cancer (Ser versus Pro: P = 0.33, OR = 1.08, 95% CI = 0.92-1.28; Ser/Ser versus Pro/Pro: P = 0.58, OR = 1.16, 95% CI = 0.68-2.00; Ser/Ser versus Pro/Ser + Pro/Pro: P = 0.62, OR = 1.14, 95% CI = 0.68-1.90; Ser/Ser + Pro/Ser versus Pro/Pro: P = 0.30, OR = 1.07, 95% CI = 0.94-1.22). In the stratified analysis by ethnicity, we found that the Pro187Ser polymorphism was associated with increased breast cancer risk in Caucasians in the additive genetic model and dominant genetic model (P = 0.03, OR = 1.13, 95% CI = 1.01-1.26; P = 0.03, OR = 1.15, 95% CI = 1.01-1.30, respectively), whereas no significant in Asians (P = 0.44, OR = 0.94, 95% CI = 0.80-1.10) and postmenopausal women (P = 0.99, OR = 1.00, 95% CI = 0.84-1.19). The results suggest that NQO1 Pro187Ser polymorphism may contribute to breast cancer development in Caucasians.

LFA-1 gene polymorphisms are associated with the sporadic infiltrative duct breast carcinoma in Chinese Han women of Heilongjiang Province.

The infiltrative duct carcinoma (IDC) is the most common malignant breast cancer in females and genetic factors appear to play a significant role in the susceptibility of IDC. The LFA-1 is a crucial co-stimulatory molecule in immune system and may affect the development of breast IDC. In order to clarify the association of LFA-1 polymorphisms with IDC, a case-control study was conducted in women from Heilongjiang Province, Northeast of China. We scrutinized four genetic polymorphisms in LFA-1 gene, which may influence the activity and function of LFA-1. Our research subjects consist of 537 cases with IDC and 577 age-matched healthy controls. Genotypes were determined by PCR-RFLP. Data were analyzed using the χ(2) test by SPSS 13.0 and Haploview 4.1 softwares. The association between LFA-1 polymorphisms and the clinical features of IDC was analyzed. In rs2230433, the frequency of GG genotype and G allele was lower in cases than in controls (P = 0.0316 and 0.0480). And rs2230433, CG genotype was higher in cases (P = 0.0397). In rs8058823, the frequency of AA genotype and A allele was lower in cases than in controls (P = 0.00000418 and 0.00000267). And rs8058823, AG genotype was higher in cases (P = 0.00000747). The frequency of haplotype CCGA was lower in patients. Significant association was shown between the four SNPs of LFA-1 gene and estrogen receptor (ER), progesterone receptor (PR), C-erbB-2, and P53 statuses. In addition, no association was found between LFA-1 gene polymorphisms and tumor size, and neither was it between LFA-1 gene polymorphisms and lymph node metastasis. Our results primarily suggested that LFA-1 gene polymorphisms may predict the sporadic breast IDC risk and prognosis factors in Chinese Han women in Heilongjiang Province.

PD-1 polymorphisms are associated with sporadic breast cancer in Chinese Han population of Northeast China.

The programmed death-1 (PD-1) is a potent immunoregulatory molecule which is responsible for the negative regulation of T-cell activation and peripheral tolerance. In order to investigate the association between polymorphisms of PD-1 and breast cancer, a case-control study was conducted in Chinese female population consisting of 490 cases with breast cancer and 512 age-matched healthy individuals from Heilongjiang Province of China. Four polymorphisms of the PD-1 gene, including rs36084323 (PD-1.1), rs7421861, rs2227982 (PD-1.9), and rs2227981 (PD-1.5), were selected and genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The frequencies of PD-1.1 GG genotype and PD-1.5 CT genotype were significantly lower in cases compared with controls (P = 0.020 and 0.004, respectively), and PD-1.5 CC genotype and C allele had higher frequencies in cases (P = 0.003 and 0.010). In haplotype analysis, we observed that the frequencies of ATTC and GTCT haplotypes were lower in cases than those of in controls (P = 0.0055 and 0.0012, respectively), whereas the GTCC and ATCC haplotypes had higher frequencies in cases (P = 0.0040 and 0.00008037, respectively). Additionally, strong association was showed between PD-1.1 and P53, and haplotype CCTA was associated with ER status. These results primarily suggest that PD-1 gene polymorphisms may affect the breast cancer risk and prognosis in Chinese Han females of Heilongjiang Province in Northeast China.

ICOS gene polymorphisms are associated with sporadic breast cancer: a case-control study.

BACKGROUND: Inducible costimulator (ICOS), a costimulatory molecular of the CD28 family, provides positive signal to enhance T cell proliferation. Its abnormal expression can disturb the immune response and entail an increased risk of cancer. To investigate whether single nucleotide polymorphisms (SNPs) in the ICOS gene are associated with sporadic breast cancer susceptibility and progression in Chinese women, a case-control study was conducted. METHODS: In the study cohort, we genotyped five SNPs (rs11889031, rs10932029, rs4675374, rs10183087 and rs10932037) in ICOS gene among 609 breast cancer patients and 665 age-matched healthy controls. Furthermore, the positive results were replicated in an independent validation cohort of 619 patients and 682 age-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotypes. RESULTS: In rs10932029, compared with TT genotype and T allele, the CT genotype and C allele showed a significantly increased risk of breast cancer (P = 0.030, OR = 1.467, 95% CI 1.037-2.077; P = 0.017, OR = 1.481, 95% CI 1.070-2.049, respectively), and the associations were also significant in the validation cohort (P = 0.002, OR = 1.693, 95% CI 1.211-2.357; P = 0.003, OR = 1.607, 95% CI 1.171-2.204, respectively). Haplotype analysis showed that CTCAC haplotype containing rs10932029 T allele had a lower frequency in cases than in controls (P = 0.015), whereas haplotype CCCAC containing rs10932029 C allele was more common in cases than in controls (P = 0.013). In the analysis of clinicopathologic features, rs11889031 CT genotype and T allele were associated with progesterone receptor (PR) status and lymph node metastasis, which were further supported by our validation cohort. Moreover, some haplotypes were associated with estrogen receptor (ER) and PR statuses. CONCLUSIONS: These results indicate that ICOS gene polymorphisms may affect the risk of breast cancer and show that some SNPs are associated with breast cancer characteristics in a northern Chinese population.

Association of BTLA gene polymorphisms with the risk of malignant breast cancer in Chinese women of Heilongjiang Province.

B and T lymphocyte attenuator (BTLA) is an immunoinhibitory receptor with the ability to deliver inhibitory signals for suppressing lymphocyte activation. To identify the influences of BTLA gene polymorphisms on the risk of sporadic breast cancer, a case-control study was conducted in women from northeast of China, Heilongjiang Province. We genotyped five SNPs (rs9288952, rs2931761, rs2633562, rs2705535 and rs1844089) in BTLA gene among exons and introns. Our research groups consist of 592 patients with breast cancer and 506 age/sex-matched healthy controls. Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and polymerase chain reaction with confronting two-pair primer (PCR-CTPP) methods. Data were analyzed using the chi-square test by EXCEL, SPSS and Haploview softwares. The frequencies of BTLA rs1844089 CT and rs2705535 AG were higher in patients than in controls (P = 0.0164; P = 0.0031), and rs1844089 CC, rs2705535 GG and rs9288952 CC genotypes had lower incidences in patients than in controls (P = 0.0483; P = 0.0098; P = 0.0400). The frequency of haplotype CAAAT was significantly higher in patients (P = 0.0112). Strong association was shown between five SNPs of BTLA gene and tumor size, estrogen receptor (ER), progesterone receptor (PR), C-erbB-2 and P53 statuses. Strong association was observed between tumor size, ER, PR, P53 and the CAGAT(P = 0.012), TAAGT(P = 0.0378), CAGAT(P = 0.0013), CAAGT(P = 0.0373) and CAAAT(P = 0.0306) haplotypes. These results primarily suggested that BTLA gene polymorphisms may affect the sporadic breast cancer risk and prognosis in Chinese women in northeast of Heilongjiang Province.

B7-H4 gene polymorphisms are associated with sporadic breast cancer in a Chinese Han population.

BACKGROUND: B7-H4, a co-inhibitory molecule of the B7 family, can restrain T cell proliferation, cytokine secretion and the development of cytotoxicity. B7-H4 is expressed in tumor tissues at a higher level than in normal tissues, and has a potential effect to protect tumors from anti-tumor immune responses. This case-control study was carried out to determine the potential influences of B7-H4 gene polymorphisms on the susceptibility and progression of breast cancer in Han women of Northeast China. METHODS: We genotyped three B7-H4 variants (rs10754339, rs10801935 and rs3738414) and tagged all common haplotypes (frequency greater than or equal to 1%) in a Chinese population consisting of 500 breast cancer cases and 504 control individuals matched for age. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to determine the genotypes. RESULTS: Our data indicated that, compared with the common genotype and allele of each SNP, the rs10754339 AG genotype and G allele showed a significantly increased risk of breast cancer (OR = 1.455, 95% CI 1.119-1.892; OR = 1.325, 95% CI 1.073-1.637, respectively). The rs10801935 CC genotype, the rs3738414 AA genotype and the rs3738414 A allele were associated with a significantly decreased risk of breast cancer (OR = 0.328, 95% CI 0.145-0.739; OR = 0.412, 95% CI 0.203-0.835; OR = 0.698, 95% CI 0.564-0.864, respectively). Additionally, the rs10754339 GG genotype was significantly associated with lymph node metastasis and PR status, and the G allele and the AG genotype were respectively associated with lymph node metastasis and ER status. In haplotype analysis, we observed that compared with the AAG haplotype, the AAA haplotype showed a significantly decreased risk of breast cancer (OR = 0.689, 95% CI 0.539-0.881), but the GAG haplotype was associated with a significantly increased risk of breast cancer (OR = 1.511, 95% CI 1.125-2.031). And the AAA and the GCG haplotypes also respectively have significant influences on tumor size and ER status. CONCLUSION: These results suggest that B7-H4 gene polymorphism may contribute to the sporadic breast cancer risk and prognosis in Chinese Han women.