Peptide inhibition of cytokine-stimulated aromatase activity in breast tissue fibroblasts

The cytokine interleukin-6 (IL-6) and its soluble receptor (IL-6sR) can act synergistically to stimulate aromatase activity in cultured stromal fibroblasts derived from breast tissues. In this study, a 16 amino acid peptide, AROHIB, has been used in an attempt to block the ability of IL-6 plus IL-6sR to stimulate aromatase activity in stromal fibroblasts. Pre-incubation of cells with AROHIB for a 3-h period before the addition of IL-6 and IL-6sR resulted in a marked (67%) reduction in the ability of these factors to stimulate aromatase activity. AROHIB was found to be rapidly degraded when exposed to MCF-7 breast cancer cells or fibroblasts. Analysis by FAB-MS was used to identify the site of peptide cleavage. Subsequently, a series of 10 amino acid peptides, DP1-DP4, were designed, synthesised and tested for their ability to resist proteolytic degradation and to inhibit IL-6 plus IL-6sR-stimulated aromatase activity. Peptide DP2, a modified version of the active fragment of AROHIB, had N-acetyl and C-amino terminal protection and an internal D-amino acid (instead of L form) at the site of proteolytic cleavage. Using cells cultured in the presence of 2% stripped foetal calf serum, peptide DP2 resulted in a 74% reduction in cytokine-stimulated aromatase activity. Under serum-free conditions, peptides DP1-DP3 showed modest inhibitory properties. Results from this study suggest that it may be possible to develop small peptides to inhibit cytokine-stimulated aromatase activity in a tissue-specific manner.     

Studies on the Methylation Status of CpG Sequences Located in Promoters of Selected Tumour Suppressor Genes in Breast Cancer Cells

In the tested samples of sporadic breast cancer (100 cases), hypermethylation of CpG sequences located in ERα promoter was observed in 62 cases. It correlated with: (i) deficiency of ERα protein in 45%, (ii) hypermethylation of BRCA1 promoter in 95%, and (iii) nonmethylated E-cadherin promoter in 90%. Fifty-eight percent of the patients with nonmethylated E-cadherin promoter (56 cases) did not show metastasis to lymphatic nodes. The analysis of the methylation level of the promoter of ERα, BRCA1, and E-cadherin, frequently connected with their activity, shows that it can be an important parameter in the diagnosis and therapeutic strategies in sporadic breast cancer.     

Prognostic factors and survival in metastatic breast cancer: A single institution experience

Background

The current retrospective study aims to identify some determinants of survival in metastatic breast cancer.

Methods

The study concerned 332 patients with synchronous (SM) or metachronous (MM) metastatic breast cancer treated between January 2000 and December 2007. Statistical comparison between subgroups of patients concerning survival was carried out employing log-rank test for the invariable analysis and Cox model for the multivariable analysis. Factors included: age group (≤50 years vs. >50; ≤70 years vs. >70; ≤35 years vs. >35), menopausal status, presentation of metastatic disease (SM vs. MM), disease free interval (DFI) (≤24 months vs. >24 months; ≤60 months vs. >60 months), performance status at diagnosis of metastatic disease (PS) (0–1 vs. >1), hormone receptors (HR), number of metastatic sites (1 site vs. >1), nature of the metastatic site (visceral vs. non visceral), first line therapy, surgery of the primary tumor (SPT), locoregional radiotherapy (LRRT) and use or not of bisphosphonates.

Results

Overall survival at 5 years was 12%. Positive prognostic factors in univariate analysis were: age ≤ 70 years, hormono-dependence of the tumor, good PS (PS 0–1), less than two metastatic sites, no visceral metastases, DFI ≥ 24 months, SPT or LRRT. In multivariate analysis, favorable independent prognostic factors included: good PS (PS 0–1), absence of visceral metastases (liver, lung, brain) and age ≤ 70 years.

Conclusion

Many of the prognostic factors in metastatic breast cancer found in our study are known in the literature but some of them, like the application of locoregional treatment (radiotherapy or surgery) and the use of bisphosphonates, need to be further investigated in randomized clinical trials.     

乳腺癌功能磁共振成像与生物学预后因子的研究进展

乳腺癌已成为女性最为常见的恶性肿瘤,如何对乳腺癌进行早期诊断、合理化治疗及判断预后意义重大。雌激素受体(ER)、孕激素受体(PR)、Ki-67、人表皮生长因子受体2(HER-2)等免疫组化指标在判断乳腺癌临床类型、转移情况及预后等方面具有重要作用。随着功能磁共振的发展,氢质子磁共振波谱(1H-MRS)、动态增强磁共振成像(DCE-MRI)、扩散加权成像(DWI)等被越来越广泛的用于乳腺组织的检查。研究功能磁共振与乳腺癌预后因子的相关性,对乳腺癌的临床分型、治疗及预后等方面有一定的指导作用。本文就相关进展进行综述。     

Glutathione S-transferase T1 polymorphism is associated with breast cancer susceptibility

The association between present/null polymorphism of glutathione S-transferase T1 (GSTT1) and breast cancer risk are still inconclusive. We performed a meta-analysis to derive a more precise estimation of the relationship. A total of 48 studies including 17,254 cases and 21,163 controls were involved in this meta-analysis. When all studies were pooled into the meta-analysis, significantly elevated breast cancer risk was associated with null genotype (OR = 1.138, 95% CI = 1.051–1.232). When stratified by ethnicity, significantly increased risks were found for Caucasians (OR = 1.185, 95% CI = 1.075–1.306), but no statistically significantly increased risks were found in Asians (OR = 1.017, 95% CI = 0.846–1.223) and Africans (OR = 1.160, 95% CI = 0.815–1.650). In the subgroup analysis by controls source, statistically significantly elevated risks were both found in population-based studies (OR = 1.123, 95% CI = 1.014–1.243) and hospital-based studies (OR = 1.181, 95% CI = 1.056–1.321). When stratified by menopausal status, no statistically significantly increased risks were found in premenopausal women (OR = 1.115, 95% CI = 0.925–1.345) and postmenopausal women (OR = 1.077, 95% CI = 0.992–1.169). In summary, this meta-analysis suggests that the GSTT1 null genotype is a risk allele for breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.     

IL-1，IL-6，IL-8 与胃癌的关系

胃癌是常见的恶性肿瘤之一,在我国其发病率居各类肿瘤前列,导致的死亡人数占所有肿瘤的四分之一,而且每年有近40万新增的胃癌病人,但是其早期诊断率低于20%,胃癌已经成为危害人民健康的最严重的疾病之一。白细胞介素(interleukin,IL)作为在白细胞或免疫细胞间相互作用的淋巴因子,不仅在介导T、B细胞活化、增殖与分化以及炎症反应中起着重要作用,近年来,越来越多的学者发现其与肿瘤的发生及发展也有着密不可分的联系。目前为止,已经发现了29种白细胞介素,分别被命名为IL-1~IL-29,它们各自承担着相应的使命。国内外大量实验及文献表明,IL-1,IL-6,IL-8和胃癌有着密切的关系,这对于胃癌的早期诊断及治疗提出了新的思路,进而提高胃癌的早期诊断率,改善胃癌的治疗状况。本文对IL-1,IL-6,IL-8的来源、分子结构及受体方面进行简要概述,同时阐述了其生物学特性及与胃癌的关系。     

北方汉族人群白细胞介素-6基因-572C/G单核苷酸多态性与冠心病的相关性研究

目的:探讨中国北方汉族人群中白细胞介素-6(IL-6)基因启动子区-572C/G单核苷酸多态性与冠心病的关系。方法:采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,检测434例冠心病(冠心病组)患者和417名非冠心病人(对照组)的IL-6基因型,探讨-572C/G单核苷酸多态与冠心病的关系。结果:IL-6基因-572C/G多态位点的CC、CG和GG基因型在冠心病组中分别为59.68%、37.09%、3.23%,等位基因频率C和G分别为78.23%、21.77%;在健康成年者中基因型分别为67.87%、30.22%、1.92%,等位基因频率C和G分别为82.97%、17.03%。IL-6基因-572C/G位点多态性在两组人群中的分布差异存在显著性(P<0.05);经Logsitic回归校正性别、年龄、体重指数、高血压病、糖尿病、高胆固醇血症及吸烟等冠心病易患因素后,IL-6基因-572C/G单核苷酸多态是冠心病发病的独立的危险因素(P<0.05);等位基因频率的相对风险分析发现,G等位基因携带者患冠心病的风险是C等位基因的1.356倍〔OR=1.356,95%CI=1.0648～1.7279〕。...     

Tartrate-resistant acid phosphatase 5b as a serum marker of bone metastasis in breast cancer patients

Diagnosis and follow-up of bone metastases in breast cancer patients usually rely on symptoms and imaging studies. Tartrate-resistant acid phosphatase 5b (TRACP 5b) is a specific marker of osteoclasts and is herein proposed as a marker of bone metastasis in breast cancer patients. An immunoassay using a monoclonal antibody, 14G6, was used to measure the activity of serum TRACP 5b at pH 6.1 in 30 early breast cancer patients without bone metastasis and in 30 aged-matched breast cancer patients with bone metastasis. Another 60 normal volunteers were recruited as controls. Bone alkaline phosphatase (BAP), a traditional marker of bone turnover, was also measured in selected cases. The overall mean TRACP 5b activity in normal women was 2.83 ± 1.1 U/I, and it increased with age. The mean TRACP 5b activity in early breast cancer patients did not differ from that of the normal group (2.93 ± 0.64 vs. 2.83 ± 1.1 U/I; p=0.66), whereas it was significantly higher in breast cancer patients with bone metastasis (5.42 ± 2.5 vs. 2.83 ± 1.1 U/I; p<0.0001). BAP activity was significantly higher in breast cancer patients with bone metastasis than in early breast cancer patients (p=0.004). Serum TRACP 5b activity correlated well with BAP activity in breast cancer patients with bone metastasis (p<0.0001), but not in normal individuals or in patients without bone metastasis. TRACP 5b activity can be considered a surrogate indicator of bone metastasis in breast cancer patients.     

GAEC1 mutations and copy number aberration is associated with biological aggressiveness of colorectal cancer

GAEC1 (gene amplified in oesophageal cancer 1) is a transforming oncogene with tumorigenic potential observed in both oesophageal squamous cell carcinoma and colorectal cancer. Nonetheless, there has been a lack of study done on this gene to understand how this gene exert its oncogenic properties in cancer. This study aims to identify novel mutation sites in GAEC1. To do so, seventy-nine matched colorectal cancers were tested for GAEC1 mutation via Sanger sequencing. The mutations noted were investigated for the correlations with the clinicopathological parameters of the patients with the cancer. Additionally, GAEC1 copy number aberration (CNA), mRNA and protein expression were determined with the use of droplet digital (dd) polymerase chain reaction (PCR), real-time PCR and Western blot (confirmed with immunofluorescence analysis). GAEC1 mutation was noted in 8.8% (n?=?7/79) of the cancer tissues including one missense mutation, four loss of heterozygosity (LOH) and two substitutions. These mutations were significantly associated with cancer perforation (p?=?0.021). GAEC1 mutation is frequently associated with increased GAEC1 protein expression. Nevertheless, GAEC1 mRNA and protein are only weakly associated. Taken together, GAEC1 mutation affects GAEC1 expression and is associated with poorer clinical outcomes. This further strengthens the role of GAEC1 as an oncogene.     

Luminal (Her2 negative) prognostic index and survival of breast cancer patients

PurposeThe group of luminal (Her2 negative) is distinguished from other subtypes of breast cancer. We aimed to produce a prognostic index specific for luminal (Her2 negative) subtype breast cancer that could assist clinical treatment.MethodsThe test set comprised 406 consecutive luminal (Her2 negative) breast cancer patients. The relationship of 11 clinicopathologic factors including survivin with the 5-year disease-free survival was analyzed.ResultsIn univariate analysis, TNM stage, surgery, tumor size, lymph node involvement, and survivin expression were prognostic factors. In multivariate analysis, tumor size [HR (95% CI): 1.98 (1.12–3.49), p = 0.019], the number of lymph node metastasis [HR (95% CI): 1.75 (1.33–2.29), p < 0.0001] and the expression of progesterone receptor [HR (95% CI): 0.58 (0.36–0.95), p = 0.029] can independently predict prognosis. Prognostic index (PI) was calculated as 0.68 × tumor size + 0.56 × the number of lymph node metastasis − 0.54 × PR. According to the PI, patients were categorized into three groups: low, middle, and high risk group with the 5-year disease-free survival rates of 91.91%, 84.97% and 70.47%, respectively (P < 0.001). In the validation set, the luminal prognostic index (LPI) remained significant.ConclusionThe LPI may be a useful tool for evaluating the outcome of patients with luminal (Her-2 negative) breast cancer.     

SHCBP1:乳腺癌治疗候选靶点和潜在预后标志物

探讨SHCBP1在乳腺癌及其不同亚型中的表达特征和预后价值。利用Oncomine, bc-GenExMiner v4.2, Kaplan-Meier plotter, GSE41994及STRING数据库分析乳腺癌病人SHCBP1的mRNA表达水平及其与乳腺癌患者生存率的相关性等。结果:(1)乳腺癌组织中SHCBP1的mRNA水平明显高于正常组织样本,但不同分子亚型的乳腺癌患者中SHCBP1的表达水平不同;(2)SHCBP1表达升高可导致Luminal A亚型更短的无转移生存期(Distant metastasis-free survival,DMFS)和无病生存期(Disease-free survival, DFS);(3)在雌激素受体阳性(ER+)、孕酮受体阳性(PR+)亚型、仅接受辅助化疗、仅接受辅助化疗的ER(+)与接受包括或排除内分泌治疗乳腺癌患者中,SHCBP1表达升高则无复发生存率(Relapse-free survival,RFS)显著缩短;(4)SHCBP1和CDC45 mRNA表达水平之间呈正相关,并可能与KIF23等10种蛋白相互作用。结论:SHCBP1是一种很有前景的乳腺癌预后指标和潜在的治疗靶点。     

IL-6基因多态性与小儿全身炎症反应综合征的相关性研究

目的探讨白细胞介素-6（Interleuk in-6,IL-6）基因多态性与小儿全身炎症反应综合征（system ic inflamm atory response syndrom e,SIRS）的关系。方法 30例SIRS患儿为SIRS组,随机挑选30例健康体检的小儿为对照组,采用限制片段长度多态分析聚合酶链反应方法（PCR/RFLP）对2组儿童的IL-6基因的-174位点和-572位点基因进行分析;并应用酶联免疫吸附试验法（ELISA）检测2组儿童的血清IL-6水平,观察基因型对血清IL-6水平的影响。结果 IL-6基因-572位点基因型和等位基因频率在2组间分布差异有统计学意义,SIRS组GG基因型和G等位基因频率均显著高于对照组（P〈0.05）;携带G等位基因个体患SIRS的风险约是C等位基因型个体的6.84倍（OR95%CI：2.62～17.89,P〈0.05）;G等位基因携带者IL-6血清含量显著高于CC基因携带者（P〈0.05）。IL-6基因启动子-174位点在SIRS组与对照组中只发现GG基因型,CG和CC基因型在2组中均未发现;SIRS组IL-6血清水平显著高于对照组（P〈0.05）。结论 IL-6基因-572C/G多态性可能是中国汉族儿童SIRS发病的遗传危险因素之一,血清IL-6水平可能受其基因多态性的影响。而IL-6基因-174G/C多态性与中国汉族儿童SIRS发病可能不具有相关性。