Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

In a previous study from our laboratory, high tumor levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) have been associated with an adverse response to chemotherapy in metastatic breast cancer suggesting that TIMP-1, which is known to inhibit apoptosis, may be a new predictive marker in this disease. The purpose of this study was to investigate the association between TIMP-1 and objective response to chemotherapy in an independent patient population consisting of patients with metastatic breast cancer from Sweden and Denmark. TIMP-1 was measured using ELISA in 162 primary tumor extracts from patients who later developed metastatic breast cancer and these levels were related to the objective response to first-line chemotherapy. Increasing levels of TIMP-1 were associated with a decreasing probability of response to treatment, reaching borderline significance (OR = 1.59, 95% CI: 0.97–2.62, P = 0.07). This OR is very similar to the result from our previous study. Increasing levels of TIMP-1 were also associated with a shorter disease-free survival and overall survival, however, not statistically significant. The results from the present study support previous data that TIMP-1 is associated with objective response to chemotherapy for metastatic breast cancer.     

Durable response of breast cancer leptomeningeal metastasis to capecitabine monotherapy

We report a durable (12-month) response to capecitabine monotherapy, shown clinically, by MRI, and by cerebrospinal fluid analysis, in a patient with leptomeningeal metastasis from breast cancer.     

Association between c-myc amplification and pathological complete response to neoadjuvant chemotherapy in breast cancer

Background

The aim of this study was to investigate whether c-myc amplification in human breast cancer is associated with response to neoadjuvant chemotherapy comprising paclitaxel followed by 5-FU/epirubicin/cyclophosphamide (P-FEC).

Methods

Tumour tissue samples were obtained before neoadjuvant chemotherapy (P-FEC) from 100 primary breast cancer patients (stage II/III). C-myc and HER2 amplification were examined by FISH, and oestrogen receptor (ER), progesterone receptor (PR), Ki67, and topoisomerase 2α (TOP2A) expression were examined immunohistochemically. Pathological complete response (pCR) was defined by a complete loss of tumour cells in the breast without any lymph node metastasis.

Results

C-myc amplification was observed in 40% (40/100) of breast tumours, and was significantly associated with ER-negative tumours (23/40 for ER(-) versus 17/60 for ER(+), P = 0.004), high histological grade tumours (11/18 for grade 3 versus 29/82 for grades 1 + 2, P = 0.043) and TOP2A-positive tumours (28/51 for TOP2A(+) versus 12/49 for TOP2A(-), P = 0.002). pCR rate was 20% for total patients (10.0% for ER(+) and 35.0% for ER(-)). Further, breast tumours with c-myc amplification (c-myc(+)) showed a significantly (P = 0.041) higher pCR rate (12/40) than those without such amplification (c-myc(-)) (8/60). This association between pCR and c-myc amplification was observed in ER-positive tumours (4/17 for c-myc(+) versus 2/43 for c-myc(-), P = 0.048) but not in ER-negative tumours (8/23 for c-myc(+) versus 6/17 for c-myc(-), P = 0.973).

Conclusion

Our results suggest that c-myc amplification is significantly associated with a high pCR rate to P-FEC in breast tumours, especially in ER-positive tumours.     

Association between high-risk HPV types, HLA DRB1* and DQB1* alleles and cervical cancer in British women

Cervical scrapes from 116 British women referred with cervical cancer were tested for the presence of high oncogenic risk human papillomavirus (HPV) genotypes (HPV(hr)). Ninety-four per cent of the scrapes had one or more of these virus types and 66% were HPV16-positive. HPV18 was more frequent in adenocarcinoma. No evidence was found for an increased cancer risk associated with the HPV16 E6 350G variant. The HLA DRB1* and DQB1* alleles in these women and in 155 women with normal cytology and negative for HPV(hr) DNA were compared. DQB1*0301 alone (2P = 0.02) and in combination with DRB1*0401 (2P = 0.02) was found to be associated with cervical cancer. This was more marked in cancers positive for HPV types other than HPV16. In contrast, DRB1*1501 alone and in combination with DQB1*0602 was not significantly elevated in cancers overall, but did show some excess in HPV16-positive cancers (2P = 0.05), associated with HPV16-positive cervical cancers. Taking all cancers together, a marginally significant protective effect was found for DQB1*0501 (2P = 0.03) but no protective effect could be seen for DRB1*1301.     

Association between CYP2E1 polymorphisms and susceptibility to prostate cancer.

Several genetic alterations have been associated with sporadic prostate cancer (PCa). In this study, the association between RsaI and DraI polymorphisms of CYP2E1 and PCa risk was analysed in a case-control study of 227 individuals using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Regarding DraI polymorphisms, the DD genotype is over-represented in PCa cases when compared with the control group (odds ratio (OR) 2.12; 95% confidence interval (CI) 1.11-4.05; P=0.022). Regarding the RsaI polymorphism, no significant differences were found. The results of this study indicate that DraI polymorphisms of the CYP2E1 gene may be associated with a twofold increased risk for the development of PCa.     

A case of recurrent breast cancer with multiple lung metastases responding to anastrozole monotherapy

A 51-year-old postmenopausal woman was referred to our hospital for treatment of ER-positive recurrent breast cancer. The patient had lung and pleural metastases with pleural effusion from breast cancer. She was treated with anastrozole, a 3rd-generation aromatiase inhibitor. The efficacy of the treatment was definite: the multiple metastatic lung lesions showed a partial response after 5 months' treatment, and reached a complete response after 14 months' treatment. The patient experienced no adverse effects with this therapy. Anastrozole therapy is a useful treatment for postmenopausal woman with ER-positive recurrent breast cancer.     

MDR1基因多态性与其在乳腺癌患者中表达水平的关系

目的:探讨MDR1基因多态性与其在乳腺癌患者癌组织中表达水平的关系。方法:筛选93例乳腺癌组织及26例配对癌旁组织,利用PCR-RFLP技术检测MDR1 exon12(1236)、exon21(2677)、exon26(3435)3个位点的多态性,以RT-qPCR技术对MDR1 mRNA进行相对定量,分析不同基因型患者间MDR1基因的表达水平。结果:93例乳腺癌组织中均有不同程度MDR1基因的表达;C1236T、G2677T/A和C3435T各基因型与MDR1表达水平之间均未显示统计学差异(F=0.047,P=0.954;F=0.364,P=0.833和F=0.173,P=0.841);但其中2 6例癌组织MDR1 mRNA表达水平,明显高于其对应的癌旁组织(3.83±5.27 vs 1.81±4.42;t=2.522,P=0.018)。结论:癌组织可能易发生多药耐药,MDR1表达差异的遗传学基础还有待进一步研究。     

雌激素受体基因ESR1多态性与乳腺癌易感性的关系

目的：研究雌激素受体α（ESR1）基因单核苷酸多态性（SNPs）与乳腺癌易感性的关系。方法：运用聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）分析的方法检测193例中国汉族女性乳腺癌患者和71名正常女性对照者ESR1基因上rs11155816位点的基因型,以SPSS 11.0软件卡方检验处理数据。结果：rs11155816位点等位基因频率符合Hardy-Weinberg遗传平衡定律。rs11155816位点的等位基因及基因型与患者肿瘤位置及是否存在远处转移相关,差异有显著性（P〈0.05）;与年龄、大小、组织学类型、受体表达无关。rs11155816位点等位基因及基因型频率在乳腺癌人群与正常对照者间分布差异有显著性,乳腺癌人群中等位基因A频率高于正常人群（23.8%比15.5%,P〈0.05）。结论：rs11155816位点基因的多态性与乳腺癌患者的肿瘤位置和远处转移相关,等位基因A携带者乳腺癌发病风险较高。     

雌激素受体基因ESR1多态性与乳腺癌易感性的关系

目的:研究雌激素受体α(ESR1)基因单核苷酸多态性(SNPs)与乳腺癌易感性的关系。方法:运用聚合酶链反应(PCR)和限制性片段长度多态性(RFLP)分析的方法检测193例中国汉族女性乳腺癌患者和71名正常女性对照者ESR1基因上rs11155816位点的基因型,以SPSS 11.0软件卡方检验处理数据。结果:rs11155816位点等位基因频率符合Hardy-Weinberg遗传平衡定律。rs11155816位点的等位基因及基因型与患者肿瘤位置及是否存在远处转移相关,差异有显著性(P<0.05);与年龄、大小、组织学类型、受体表达无关。rs11155816位点等位基因及基因型频率在乳腺癌人群与正常对照者间分布差异有显著性,乳腺癌人群中等位基因A频率高于正常人群(23.8%比15.5%,P<0.05)。结论:rs11155816位点基因的多态性与乳腺癌患者的肿瘤位置和远处转移相关,等位基因A携带者乳腺癌发病风险较高。     

DNA连接酶基因LIG1多态性与肺癌易感性研究

背景与目的: 肺癌是由环境和遗传两大类因素联合作用导致的复杂疾病,其中DNA损伤是肺癌遗传病因中的重要组分.作为参与多条DNA损伤修复通路的关键因子,DNA连接酶与肺癌发生可能存在联系.本文旨在研究DNA连接酶基因LIG1外显子6多态性与肺痛易感性的关系,并探索其与吸烟可能的交互作用.方法: 采用病例-对照研究,收集原发性肺癌患者396例为病例组,同时随机抽取465名当地健康居民作为对照组,进行流行病学调查.运用PCR-RFLP方法分析LIG1基因外显子6的多态性.应用Logistic回归模型分析该位点多态性与肺癌易感性的关系.结果: 突变等位基因C在病例组和对照组中的频率分别为28.41%和26.02%,两组间差异无显著性(P=0.2667).相对于野生型A/A,携带A/C基因型者患肺癌的危险度为1.20(95%CI:0.90～1.62);而患肺腺癌和肺鳞癌的危险度分别达到1.45(95%CI:0.93～2.26)和1.57(95%CI:0.93～2.65).在肺腺癌的发病中,LIGI多态的突变基因型与吸烟之间存在临界显著的负交互作用(OR=0.44,95%CI=0.18～1.06).结论: DNA连接酶基因LIG1外显子6多态性可能与肺腺癌和肺鳞癌的易感性有关.     

中国汉族人群DNA聚合酶ε基因POLE1单核苷酸多态性与肺癌易感性的关系

目的：探讨人类DNA聚合酶ε基因POLE1单核苷酸多态性（SNP）与肺癌易感性间的关系。方法：采用病例对照研究方法,选择经组织学确诊的肺癌患者462例,以及相同地区,性别年龄频数匹配的对照466例,针对经筛选的5个SNP进行基因型检测,通过统计分析研究基因频率与肺癌风险的关系,并探讨吸烟在其中的影响。结果：病例组rs5744738基因频率分布高于对照组（P〈0.05）。A/A纯合变异携带人群的患肺癌风险显著降低（校正OR=0.47,95%CI：0.25～0.91）。在分层分析中,60岁以上人群患肺癌的风险显著下降（校正OR=0.28,95%CI：0.09～0.91）,无患肿瘤家族史人群下降到0.42倍（校正OR=0.42,95%CI：0.19～0.90）。随着吸烟量的增加,G/G或G/A基因型人群肺癌风险显著升高。rs5744962变异位点（T→C）可提高非吸烟人群的患肺癌风险至1.75倍（95%CI：1.02～3.00）。结论：选取的5个人类POLE1基因SNP的多态性可能与中国汉族人群肺癌遗传易感性有关,在携带rs5744738及与之紧密连锁的rs4883545、rs5744873突变纯合基因的人群,患肺癌的风险显著降低,而携带rs5744962、rs5745047突变基因位点的非吸烟人群患肺癌的风险升高。     

A case of aged recurrent breast cancer with multiple lung metastases responding to examestane monotherapy

An 85-year-old woman suffering from an angina attack was admitted to our hospital, and diagnosed with multiple lung metastases by CT scan. Because she was extremely aged with a long disease-free period of over 12 years, and without any life-threatening state despite multiple lung metastases, she received hormonal therapy. Examestane was considered one of the most-effective hormonal drugs for metastatic breast cancer. The efficacy of the treatment was definite: the multiple metastatic lesions showed a partial response after 5 months'treatment, and reached a complete response after 10 months'treatment. After 8 months in the complete response state, CT scan revealed progressive disease. Fortunately, the lung metastatic lesions were only slowly progressive, and she has no symptoms now. There was no side effect except for complication of subdural hematoma. Examestane is considered highly effective for metastatic breast cancer and well tolerated by an aged patient like this case.     

Antibiotics that target mitochondria effectively eradicate cancer stem cells,across multiple tumor types: Treating cancer like an infectious disease

Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.     

Metformin and simvastatin synergistically suppress endothelin 1-induced hypoxia and angiogenesis in multiple cancer types

Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti-angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the underlying anticancer mechanisms of antiangiogenic drugs are still unknown. Metformin (MET) and simvastatin (SVA), two metabolic-related drugs, have been shown to play important roles in modulating the hypoxic tumor microenvironment and angiogenesis. Whether the combination of MET and SVA could exert a more effective antitumor effect than individual treatments has not been examined. The antitumor effect of the synergism of SVA and MET was detected in mouse models, breast cancer patient-derived organoids, and multiple tumor cell lines compared with untreated, SVA, or MET alone. RNA sequencing revealed that the combination of MET and SVA (but not MET or SVA alone) inhibited the expression of endothelin 1 (ET-1), an important regulator of angiogenesis and the hypoxia-related pathway. We demonstrate that the MET and SVA combination showed synergistic effects on inhibiting tumor cell proliferation, promoting apoptosis, alleviating hypoxia, decreasing angiogenesis, and increasing vessel normalization compared with the use of a single agent alone. The MET and SVA combination suppressed ET-1-induced hypoxia-inducible factor 1α expression by increasing prolyl hydroxylase 2 (PHD2) expression. Furthermore, the MET and SVA combination showed a more potent anticancer effect compared with bosentan. Together, our findings suggest the potential application of the MET and SVA combination in antitumor therapy.     

Systematic analyses of glutamine and glutamate metabolisms across different cancer types

Background: Glutamine and glutamate are known to play important roles in cancer biology. However, no detailed information is available in terms of their levels of involvement in various biological processes across different cancer types, whereas such knowledge could be critical for understanding the distinct characteristics of different cancer types. Our computational study aimed to examine the functional roles of glutamine and glutamate across different cancer types. Methods: We conducted a comparative analysis of gene expression data of cancer tissues versus normal control tis-sues of 11 cancer types to understand glutamine and glutamate metabolisms in cancer. Specifically, we developed a linear regression model to assess differential contributions by glutamine and/or glutamate to each of seven biological processes in cancer versus control tissues. Results: While our computational predictions were consistent with some of the previous observations, multiple novel predictions were made: (1) glutamine is generally not involved in purine synthesis in cancer except for breast cancer, and is similarly not involved in pyridine synthesis except for kidney cancer; (2) glutamine is generally not involved in ATP production in cancer; (3) glutamine's contribution to nucleotide synthesis is minimal if any in cancer;(4) glutamine is not involved in asparagine synthesis in cancer except for bladder and lung cancers; and (5) glutamate does not contribute to serine synthesis except for bladder cancer. Conclusions: We comprehensively predicted the roles of glutamine and glutamate metabolisms in selected meta-bolic pathways in cancer tissues versus control tissues, which may lead to novel approaches to therapeutic devel-opment targeted at glutamine and/or glutamate metabolism. However, our predictions need further functional validation.     

Association between microsomal epoxide hydrolase 1 T113C polymorphism and susceptibility to lung cancer

Previous case–control studies assessing the association between microsomal epoxide hydrolase 1 (EPHX1) T113C and susceptibility to lung cancer reported conflicting results. Thus, a systemic review and meta-analysis of published studies were performed to assess the possible association. PubMed and Embase databases were searched for all eligible studies. The strength of the association between EPHX1 T113C polymorphism and lung cancer risk was estimated by the pooled odds ratios (ORs) with its 95 % confidence interval. Twenty-four individual case–control studies involving a total of 4,970 lung cancer cases and 8,917 controls were finally included into the meta-analysis. When all 24 studies were included into the meta-analysis, the pooled results suggested that there was no association between EPHX1 T113C polymorphism and lung cancer risk under all four comparison models, and all P values for the pooled ORs were more than 0.05. In the subgroup analysis of Caucasians, the pooled results suggested that EPHX1 T113C polymorphism was associated with decreased risk of lung cancer under all four comparison models, and all P values for the pooled ORs were less than 0.05. However, in the subgroup analysis of Asians, the pooled results suggested that EPHX1 T113C polymorphism was associated with increased risk of lung cancer under three comparison models, and all P values for the pooled ORs were less than 0.05. There was no risk of publication bias. This current meta-analysis suggests that EPHX1 T113C polymorphism is associated with lung cancer risk, and there is an obvious race-specific effect in the association.