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author:("Toi, masaka")
1.  Trogocytosis-mediated expression of HER2 on immune cells may be associated with a pathological complete response to trastuzumab-based primary systemic therapy in HER2-overexpressing breast cancer patients 
BMC Cancer  2015;15:39.
Trogocytosis is defined as the transfer of cell-surface membrane proteins and membrane patches from one cell to another through contact. It is reported that human epidermal growth factor receptor 2 (HER2) could be transferred from cancer cells to monocytes via trogocytosis; however, the clinical significance of this is unknown. The aim of this study is to demonstrate the presence and evaluate the clinical significance of HER2+ tumor-infiltrated immune cells (arising through HER2 trogocytosis) in HER2-overexpressing (HER2+) breast cancer patients receiving trastuzumab-based primary systemic therapy (PST).
To assess the trogocytosis of HER2 from cancer cells to immune cells, and to evaluate the up- and down-regulation of HER2 on immune and cancer cells, peripheral blood mononuclear cells from healthy volunteers and breast cancer patients were co-cultured with HER2+ and HER2-negative breast cancer cell lines with and without trastuzumab, respectively. The correlation between HER2 expression on tumor-infiltrated immune cells and a pathological complete response (pCR) in HER2+ breast cancer patients treated with trastuzumab-based PST was analyzed.
HER2 was transferred from HER2+ breast cancer cells to monocytes and natural killer cells by trogocytosis. Trastuzumab-mediated trogocytosed-HER2+ effector cells exhibited greater CD107a expression than non-HER2-trogocytosed effector cells. In breast cancer patients, HER2 expression on tumor-infiltrated immune cells in treatment naïve HER2+ tumors was associated with a pCR to trastuzumab-based PST.
HER2-trogocytosis is visible evidence of tumor microenvironment interaction between cancer cells and immune cells. Given that effective contact between these cells is critical for immune destruction of target cancer cells, this interaction is of great significance. It is possible that HER2 trogocytosis could be used as a predictive biomarker for trastuzumab-based PST efficacy in HER2+ breast cancer patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1041-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4329225  PMID: 25655677
Breast cancer; HER2; Trogocytosis; Trastuzumab
2.  Effects of zoledronic acid and the association between its efficacy and γδT cells in postmenopausal women with breast cancer treated with preoperative hormonal therapy: a study protocol 
Although the efficacy of zoledronic acid in postmenopausal women with breast cancer has been suggested, the underlying mechanism has not been fully clarified. Therefore, which patients may benefit from zoledronic acid and the optimal frequency of zoledronic acid administration are unclear. This study evaluates the effects of zoledronic acid on the tumor response in postmenopausal women with breast cancer and explores the relationship between its efficacy and γδ T cells.
This study is an open-label, multi-institutional, single-arm, phase II clinical trial. Zoledronic acid will be administered once during preoperative hormonal therapy with letrozole for 24 weeks in postmenopausal women with Estrogen Receptor (ER)-positive , Human Epidermal Growth Factor Receptor 2 (HER2)-negative, clinical T1 or T2 N0M0 breast cancer. The primary endpoint is the objective response rate measured by MRI at 12 and 24 weeks. The secondary endpoints are the associations between the frequency of Vγ2Vδ2 T cells before the administration of zoledronic acid and the objective response, the association between the frequency of Vγ2Vδ2 T cells and the Preoperative Endocrine Prognostic Index score, and the association between the frequency of Vγ2Vδ2 T cells and Ki67 (MIB-1 index).
This study is designed to determine the add-on effect of zoledronic acid during preoperative hormonal therapy and to investigate the changes of the frequency of Vγ2Vδ2 T cells after the administration of zoledronic acid to explore the potential mechanism of zoledronic acid in breast cancer patients.
Trial registration
This trial was registered at the UMIN Clinical Trials Registry as UMIN000008701.
PMCID: PMC4246451  PMID: 25421542
Zoledronic acid; Postmenopausal women; Breast cancer; γδ T cells; Letrozole
3.  Cross-National Comparison of Medical Costs Shared by Payers and Patients: A Study of Postmenopausal Women with Early-Stage Breast Cancer Based on Assumption Case Scenarios and Reimbursement Fees 
Breast Care  2013;8(4):282-288.
The objectives of this study were to estimate and cross-nationally compare the medical costs shared by payers and patients and the distributions of medical costs by cost category.
Material and Methods
We estimated the medical costs covered from definitive diagnosis to completion of treatments of early-stage breast cancer and follow-up, assuming almost identical medical care provided in Japan, the UK, and Germany. The analysis was performed from the payer's perspective. Medical costs were calculated by multiplying the unit costs by the number of units consumed, based on assumption case scenarios. The medical costs incurred by payers or patients were estimated according to the cost-sharing and the cost-bearing systems in each country.
The total medical costs in Japan were much lower than those in the UK and Germany, and these differences were mainly caused by the low costs of surgery and radiotherapy in Japan. For the base-case scenario, the co-payment in Japan (€ 3,486) was found to be 6.4-fold higher than that in Germany (€ 548). The payers in the European countries paid 2.9-fold more than those in Japan (€ ∼25,000 vs. € 8,627).
Our results will be useful for policy makers in considering how to share medical costs and how to allocate limited resources.
PMCID: PMC3808215  PMID: 24415981
Health care system; Reimbursement; Cost-sharing; Breast cancer
4.  Comparison of γδ T cell responses and farnesyl diphosphate synthase inhibition in tumor cells pretreated with zoledronic acid 
Cancer science  2013;104(5):536-542.
Exposing human tumor cells to nitrogen-containing bisphosphonates (N-BPs), such as zoledronic acid (Zol), greatly increases their susceptibility to killing by γδ T cells. Based on this finding and other studies, cancer immunotherapy using γδ T cells and N-BPs has been studied in pilot clinical trials and has shown benefits. Although Zol treatment can render a wide variety of human tumor cells susceptible to γδ T cell killing, there has not been a systematic investigation to determine which types of tumor cells are the most susceptible to γδ T cell-mediated cytotoxicity. In this study, we determined the Zol concentrations required to stimulate half maximal tumor necrosis factor-α production by γδ T cells cultured with various tumor cell lines pretreated with Zol and compared these concentrations with those required for half maximal inhibition of farnesyl diphosphate synthase (FPPS) in the same tumor cell lines. The inhibition of tumor cell growth by Zol was also assessed. We found that FPPS inhibition strongly correlated with γδ T cell activation, confirming that the mechanism underlying γδ T cell activation by Zol is isopentenyl diphosphate (IPP) accumulation due to FPPS blockade. In addition, we showed that γδ TCR-mediated signaling correlated with γδ T cell tumor necrosis factor-α production and cytotoxicity. Some lymphoma, myeloid leukemia, and mammary carcinoma cell lines were relatively resistant to Zol treatment suggesting that assessing tumor sensitivity to Zol may help select those patients most likely to benefit from immunotherapy with γδ T cells.
PMCID: PMC3755363  PMID: 23387443
isopentenyl diphosphate; lymphoma; myeloid cells; nitrogen-containing bisphosphonate; tumor
5.  Zoledronic Acid-Induced Expansion of γδ T Cells from Early-Stage Breast Cancer Patients: Effect of IL-18 on Helper NK Cells 
Human γδ T cells display potent cytotoxicity against various tumor cells pretreated with zoledronic acid (Zol). Zol has shown benefits when added to adjuvant endocrine therapy for patients with early-stage breast cancer or to standard chemotherapy for patients with multiple myeloma. Although γδ T cells may contribute to this additive effect, the responsiveness of γδ T cells from early-stage breast cancer patients has not been fully investigated. In this study, we determined the number, frequency, and responsiveness of Vγ2Vδ2 T cells from early- and late-stage breast cancer patients and examined the effect of IL-18 on their ex vivo expansion. The responsiveness of Vγ2Vδ2 T cells from patients with low frequencies of Vγ2Vδ2 T cells was significantly diminished. IL-18, however, enhanced ex vivo proliferative responses of Vγ2Vδ2 T cells and helper NK cells from patients with either low or high frequencies of Vγ2Vδ2 T cells. Treatment of breast cancer patients with Zol alone decreased the number of Vγ2Vδ2 T cells and reduced their ex vivo responsiveness. These results demonstrate that Zol can elicit immunological responses by γδ T cells from early-stage breast cancer patients but that frequent in vivo treatment reduces Vγ2Vδ2 T cell numbers and their responsiveness to stimulation.
PMCID: PMC3639312  PMID: 23151944
γδ T cells; helper NK cells; breast cancer; phosphoantigen; nitrogen-containing bisphosphonate; IL-18
6.  The global cancer genomics consortium's third annual symposium: from oncogenomics to cancer care 
Genes & Cancer  2014;5(3-4):64-70.
The Global Cancer Genomics Consortium (GCGC) is a cohesive network of oncologists, cancer biologists and structural and genomic experts residing in six institutions from Portugal, United Kingdom, Japan, India, and United States. The team is using its combined resources and infrastructures to address carefully selected, shared, burning questions in cancer medicine. The Third Annual Symposium was organized by the Institute of Molecular Medicine, Lisbon Medical School, Lisbon, Portugal, from September 18 to 20, 2013. To highlight the benefits and limitations of recent advances in cancer genomics, the meeting focused on how to better translate our gains in oncogenomics to cancer patients while engaging our younger colleagues in cancer medicine at-large. Over two hundreds participants actively discussed some of the most recent advances in the areas cancer genomics, transcriptomics and cancer system biology and how to best apply such knowledge to cancer therapeutics, biomarkers discovery and drug development, and an essential role played by bio-banking throughout the process. In brief, the GCGC symposium provided a platform for students and translational cancer researchers to share their excitement and worries as we are beginning to translate the gains in oncogenomics to a better cancer patient treatment.
PMCID: PMC4091529
Oncogenomics; Cancer Biomarkers; Cancer Therapy
7.  Antiangiogenesis Therapy for Breast Cancer: An Update and Perspectives from Clinical Trials 
The development of new blood vessels is a crucial step in breast cancer growth, progression and dissemination, making it a promising therapeutic target. Breast cancer has a heterogeneous nature and the diversity of responsible angiogenic pathways between different tumors has been studied for many years. Inhibiting different targets in these pathways has been under investigation in preclinical and clinical studies for more than decades, among which antibody against vascular endothelial growth factor is the most studied. However, the clinical impact from antiangiogenic treatment alone or in combination with standard chemotherapeutic regimens has been relatively small till today. In this review, we summarize the most clinically relevant data from breast cancer treatment clinical trials and discuss safety and efficacy of common antiangiogenic therapies as well as biological predictive markers.
PMCID: PMC3941646  PMID: 24474817
breast cancer; antiangiogenic therapy; predictive biomarker; clinical trial
8.  Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 
Annals of Oncology  2013;24(9):2206-2223.
The 13th St Gallen International Breast Cancer Conference (2013) Expert Panel reviewed and endorsed substantial new evidence on aspects of the local and regional therapies for early breast cancer, supporting less extensive surgery to the axilla and shorter durations of radiation therapy. It refined its earlier approach to the classification and management of luminal disease in the absence of amplification or overexpression of the Human Epidermal growth factor Receptor 2 (HER2) oncogene, while retaining essentially unchanged recommendations for the systemic adjuvant therapy of HER2-positive and ‘triple-negative’ disease. The Panel again accepted that conventional clinico-pathological factors provided a surrogate subtype classification, while noting that in those areas of the world where multi-gene molecular assays are readily available many clinicians prefer to base chemotherapy decisions for patients with luminal disease on these genomic results rather than the surrogate subtype definitions. Several multi-gene molecular assays were recognized as providing accurate and reproducible prognostic information, and in some cases prediction of response to chemotherapy. Cost and availability preclude their application in many environments at the present time. Broad treatment recommendations are presented. Such recommendations do not imply that each Panel member agrees: indeed, among more than 100 questions, only one (trastuzumab duration) commanded 100% agreement. The various recommendations in fact carried differing degrees of support, as reflected in the nuanced wording of the text below and in the votes recorded in supplementary Appendix S1, available at Annals of Oncology online. Detailed decisions on treatment will as always involve clinical consideration of disease extent, host factors, patient preferences and social and economic constraints.
PMCID: PMC3755334  PMID: 23917950
surgery; radiation therapy; systemic adjuvant therapies; early breast cancer; St Gallen Consensus; subtypes
9.  Novel Insights into Breast Cancer Genetic Variance through RNA Sequencing 
Scientific Reports  2013;3:2256.
Using RNA sequencing of triple-negative breast cancer (TNBC), non-TBNC and HER2-positive breast cancer sub-types, here we report novel expressed variants, allelic prevalence and abundance, and coexpression with other variation, and splicing signatures. To reveal the most prevalent variant alleles, we overlaid our findings with cancer- and population-based datasets and validated a subset of novel variants of cancer-related genes: ESRP2, GBP1, TPP1, MAD2L1BP, GLUD2 and SLC30A8. As a proof-of-principle, we demonstrated that a rare substitution in the splicing coordinator ESRP2 (R353Q) impairs its ability to bind to its substrate FGFR2 pre-mRNA. In addition, we describe novel SNPs and INDELs in cancer relevant genes with no prior reported association of point mutations with cancer, such as MTAP and MAGED1. For the first time, this study illustrates the power of RNA-sequencing in revealing the variation landscape of breast transcriptome and exemplifies analytical strategies to search regulatory interactions among cancer relevant molecules.
PMCID: PMC3722564  PMID: 23884293
10.  The Global Cancer Genomics Consortium’s Second Annual Symposium 
Genes & Cancer  2013;4(5-6):196-200.
The Second Annual Symposium of the Global Cancer Genomics Consortium (GCGC) was held at the Tata Memorial Center in Mumbai, India, from November 19 to 20, 2012. Founded in late 2010, the GCGC aims to provide a platform for highly productive, collaborative efforts on next-generation cancer research through bridging the latest scientific and technology developments with clinical oncology challenges. This year’s presenters brought together highly innovative interdisciplinary views and strategies to meet major challenges in cancer research. The symposium featured 3 major themes: OMICS approaches toward the identification of cancer molecular drivers, single-cell analysis in cancer, and clinical and translational genomics. Each theme was represented in presentations of new findings, with an obvious implication in cross-disciplinary components of OMICs and an overwhelming participation by students. In summary, the GCGC symposium provided a discussion and congregation of the latest advances in basic and translational cancer research and offered the participants with a highly cooperative network environment for future collaboration.
PMCID: PMC3782003
genomics medicine; anticancer target; cancer therapy
11.  An overview of the Japan Breast Cancer Research Group (JBCRG) activities 
Breast Cancer (Tokyo, Japan)  2013;20(4):291-295.
The purpose of this article is to describe the current status and future perspectives of the Japan Breast Cancer Research Group (JBCRG). The JBCRG was organized in 2002, with the following purpose: to plan and promote clinical trials and basic research in breast cancer domestically and multilaterally; to conduct research and surveys on domestic and foreign information on medical care for breast cancer and to diffuse and highlight such information; to improve and promote clinical technologies for breast cancer; to act as an intermediary to liaise and strengthen alliances with affiliated organizations; and, to contribute to the public welfare by improving outcomes in breast cancer. The clinical trials are led by doctors/investigators in the JBCRG. And the purpose is to establish standard treatment for patients and provide substantial evidence. The JBCRG implements international collaboration in some researches/studies. As of January 2012, fourteen trials have been closed and nine are open to recruitment.
PMCID: PMC3824386  PMID: 23494592
Clinical trials; Clinical research; Preoperative systemic therapy; Breast cancer
12.  Prediction of axillary lymph node metastasis in primary breast cancer patients using a decision tree-based model 
The aim of this study was to develop a new data-mining model to predict axillary lymph node (AxLN) metastasis in primary breast cancer. To achieve this, we used a decision tree-based prediction method—the alternating decision tree (ADTree).
Clinical datasets for primary breast cancer patients who underwent sentinel lymph node biopsy or AxLN dissection without prior treatment were collected from three institutes (institute A, n = 148; institute B, n = 143; institute C, n = 174) and were used for variable selection, model training and external validation, respectively. The models were evaluated using area under the receiver operating characteristics (ROC) curve analysis to discriminate node-positive patients from node-negative patients.
The ADTree model selected 15 of 24 clinicopathological variables in the variable selection dataset. The resulting area under the ROC curve values were 0.770 [95% confidence interval (CI), 0.689–0.850] for the model training dataset and 0.772 (95% CI: 0.689–0.856) for the validation dataset, demonstrating high accuracy and generalization ability of the model. The bootstrap value of the validation dataset was 0.768 (95% CI: 0.763–0.774).
Our prediction model showed high accuracy for predicting nodal metastasis in patients with breast cancer using commonly recorded clinical variables. Therefore, our model might help oncologists in the decision-making process for primary breast cancer patients before starting treatment.
PMCID: PMC3407483  PMID: 22695278
Breast cancer; Lymph node metastasis; Data mining; Alternating decision tree
13.  Trastuzumab Produces Therapeutic Actions by Upregulating miR-26a and miR-30b in Breast Cancer Cells 
PLoS ONE  2012;7(2):e31422.
Trastuzumab has been used for the treatment of HER2-positive breast cancer (BC). However, a subset of BC patients exhibited resistance to trastuzumab therapy. Thus, clarifying the molecular mechanism of trastuzumab treatment will be beneficial to improve the treatment of HER2-positive BC patients. In this study, we identified trastuzumab-responsive microRNAs that are involved in the therapeutic effects of trastuzumab.
Methods and Results
RNA samples were obtained from HER2-positive (SKBR3 and BT474) and HER2-negetive (MCF7 and MDA-MB-231) cells with and without trastuzumab treatment for 6 days. Next, we conducted a microRNA profiling analysis using these samples to screen those microRNAs that were up- or down-regulated only in HER2-positive cells. This analysis identified miR-26a and miR-30b as trastuzumab-inducible microRNAs. Transfecting miR-26a and miR-30b induced cell growth suppression in the BC cells by 40% and 32%, respectively. A cell cycle analysis showed that these microRNAs induced G1 arrest in HER2-positive BC cells as trastuzumab did. An Annexin-V assay revealed that miR-26a but not miR-30b induced apoptosis in HER2-positive BC cells. Using the prediction algorithms for microRNA targets, we identified cyclin E2 (CCNE2) as a target gene of miR-30b. A luciferase-based reporter assay demonstrated that miR-30b post-transcriptionally reduced 27% (p = 0.005) of the gene expression by interacting with two binding sites in the 3′-UTR of CCNE2.
In BC cells, trastuzumab modulated the expression of a subset of microRNAs, including miR-26a and miR-30b. The upregulation of miR-30b by trastuzumab may play a biological role in trastuzumab-induced cell growth inhibition by targeting CCNE2.
PMCID: PMC3288043  PMID: 22384020
14.  Impact of body mass index on breast cancer in accordance with the life-stage of women 
Frontiers in Oncology  2012;2:123.
A large amount of epidemiological evidence suggests that the impact of body weight on breast cancer risk should be heterogeneous throughout the life-stage of women. At birth, high weight has been positively associated with an increased risk of breast cancer. While, the body mass index (a relative body weight; BMI kg/m2) has been inversely associated with breast cancer risk among pre-menopausal women. The inverse trend had been observed in both Western and Asian population, with a relatively lower percentage of obesity and higher percentage of leanness, suggested that the inverse trend could be explained not only by the protective impact due to obesity, but also by the increased risk of breast cancer due to leanness. Among post-menopausal women, however, an elevated BMI has been positively associated with the development of breast cancer, particularly in the cases of estrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) tumors. Currently, the mechanisms underlying the heterogeneous impacts between BMI on breast cancer risk and the life-stage of women remain poorly understood. We reviewed several proposed biological mechanisms that may contribute to the various impacts of relative body weight on breast cancer risk across life-stage. We also discussed the impact of BMI upon the outcome of endocrine therapy, particularly for aromatase inhibitor, in breast cancer patients. To prevent breast cancer incidence and recurrence, the desirable BMI of women may differ throughout their life-stage. To define the underlying mechanism for the various impacts of BMI in the context of breast cancer across various female life stages, further studies will be required.
PMCID: PMC3463802  PMID: 23061041
BMI; body weight; breast cancer; estrogen receptor; progesterone receptor; risk
15.  Tumor Angiogenesis: Pericytes and Maturation Are Not to Be Ignored 
Journal of Oncology  2011;2012:261750.
Angiogenesis, an essential component of tumor growth and survival, is regulated by complex interactions between several cell types and soluble mediators. Heterogeneous tumor vasculature originates from the collective effect of the nature of carcinoma and the complexity of the angiogenic network. Although the application of angiogenesis inhibitors in some types of cancers has shown clinical benefits, predictive markers to assess treatment effects have yet to be established. In this review, we focus on tumor vessel maturity as a potential marker for evaluating treatment response.
PMCID: PMC3191787  PMID: 22007214
16.  A Novel Method for Sentinel Lymph Node Biopsy by Indocyanine Green Fluorescence Technique in Breast Cancer 
Cancers  2010;2(2):713-720.
We investigated the feasibility of sentinel lymph node (SLN) biopsy using indocyanine green (ICG) technique in 411 patients with early breast cancer at three institutes. ICG, a fluorescence source, and blue dye were injected into the subareolar area to enable real-time image-guided surgery and identification of SLN fluorescence after meticulous dissection. The subcutaneous lymphatic channels were precisely detected in all cases. SLN identification rate was 99% (408/411) with a mean of 2.3 nodes identified per patient. Thirty-nine cases (9.5%) had SLNs involved and all of them were ICG positive. Thus, the ICG technique has a high SLN identification rate comparable with that of the radioisotope method.
PMCID: PMC3835100  PMID: 24281090
sentinel lymph node; indocyanine green (ICG); fluorescence; breast cancer
17.  Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic breast cancer 
BMC Cancer  2010;10:56.
We have recently described the correlation between quantitative measures of HER2 expression or HER2 homodimers by the HERmark assay and objective response (RR), time-to progression (TTP), and overall survival (OS) in an expanded access cohort of trastuzumab-treated HER2-positive patients with metastatic breast cancer (MBC) who were stringently selected by fluorescence in situ hybridization (FISH). Multivariate analyses suggested a continuum of HER2 expression that correlated with outcome following trastuzumab. Here we investigate the relationship between HER2 expression or HER2 homodimers and OS in a clinic-based population of patients with MBC selected primarily by IHC.
HERmark, a proximity-based assay designed to detect and quantitate protein expression and dimerization in formalin-fixed paraffin-embedded (FFPE) tissues, was used to measure HER2 expression and HER2 homodimers in FFPE samples from patients with MBC. Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses.
Initial analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group.
These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC.
PMCID: PMC2837013  PMID: 20178580
18.  The reversal of recurrence hazard rate between ER positive and negative breast cancer patients with axillary lymph node dissection (pathological stage I-III) 3 years after surgery 
BMC Cancer  2008;8:323.
Prognostic factors are defined as biological or clinical measurement associated with overall survival and/or disease-free survival. Previous studies have shown that patients with estrogen receptor (ER) positive cancers have a better prognosis than patients whose cancers do not have these receptors.
This study investigated the assessment of variables in defining prognosis of 742 breast cancer women with pathological stage (pTNM) I-III diagnosed between 1980 and 2005 at the Kyoto University Hospital in Japan, by age, clinical stage (cTNM), pTNM, the numbers of positive lymph nodes (pN), and ER status.
Multivariate analysis demonstrated that pTNM and ER status were the independent prognostic factors for overall survival, and that pTNM and pN were the independent prognostic factors for disease-free survival. For the 0- to 2-year interval, the hazard of recurrence was higher for the ER-negative patients than the ER-positive patients, and beyond 3 years the hazard was higher for ER-positive patients.
The present study confirmed the previous reports which showed favorable prognosis of the patients with lesser pTNM or positive ER status. A reversal of recurrence hazard rate between ER positive and negative breast cancer patients beyond 3 years after operation was detected. The fact may indicate the importance of long term adjuvant hormone therapy for ER positive cancer patients.
PMCID: PMC2585098  PMID: 18990247
19.  Cisplatin Induces the Proapoptotic Conformation of Bak in a ΔMEKK1-Dependent Manner 
Molecular and Cellular Biology  2001;21(11):3684-3691.
In a panel of four human melanoma cell lines, equitoxic doses of cisplatin induced the proapoptotic conformation of the Bcl-2 family protein Bak prior to the execution phase of apoptosis. Because cisplatin-induced modulation of the related Bax protein was seen in only one cell line, a degree of specificity in the signal to Bak is indicated. Little is known about upstream regulation of Bak activity. In this study, we examined whether the apoptosis-specific pathway mediated by a kinase fragment of MEKK1 (ΔMEKK1) is involved in the observed Bak modulation. We report that expression of a kinase-inactive fragment of MEKK1 (dominant negative MEKK [dnMEKK]) efficiently blocked cisplatin-induced modulation of Bak and cytochrome c release and consequently also reduced DEVDase activation and nuclear fragmentation. Accordingly, expression of a kinase-active MEKK1 fragment (dominant positive MEKK) was sufficient to induce modulation of Bak in three cell lines and to induce apoptosis in two of these. dnMEKK did not block cisplatin-induced c-Jun N-terminal kinase (JNK) activation, in agreement with a specifically proapoptotic role for the ΔMEKK1 pathway. Finally, we show that reduction of Bak expression by antisense Bak reduced cisplatin-induced loss of mitochondrial integrity and caspase cleavage activity in breast cancer cell lines. In summary, we have identified Bak as a cisplatin-regulated component downstream in a proapoptotic, JNK-independent ΔMEKK1 pathway.
PMCID: PMC86999  PMID: 11340162
20.  Probiotic Beverage with Soy Isoflavone Consumption for Breast Cancer Prevention: A Case-control Study 
The purpose of this study is to evaluate how beverages containing Lactobacillus casei Shirota (BLS) and soy isoflavone consumption since adolescence affected the incidence of breast cancer. In a population-based case-control study, three hundred and six cases with breast cancer and 662 controls aged 40 to 55 were matched for age and residential area and included in the analyses. Diet, lifestyle and other breast cancer risk factors were investigated using the self-administered questionnaire and interview. Odds ratios (ORs) of BLS and soy isoflavone consumption for breast cancer incidence were independently and jointly estimated using a conditional logistic regression. The ORs of BLS consumption (≥ four times a week against < four times a week) was 0.65 and statistically significant (p = 0.048). The analysis of association between soy consumption and breast cancer incidence showed the more the isoflavone consumption is, the lower the odds of breast cancer becomes. Adjusted ORs for breast cancer in the second, the third and the fourth quartiles of soy consumption against the first quartile were 0.76, 0.53 and 0.48, respectively (trend test, p = 0.0002). The BLS-isoflavone interaction was not statistically significant; however, a biological interaction was suggested. Regular consumption of BLS and isoflavones since adolescence was inversely associated with the incidence of breast cancer in Japanese women.
PMCID: PMC3744907  PMID: 23966890
Breast cancer; Lactobacillus casei Shirota; probiotic beverage; soy isoflavones.
21.  UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α 
Nature Communications  2015;6:6153.
Hypoxia-inducible factor 1 (HIF-1) plays a role in tumour metastases; however, the genes that activate HIF-1 and subsequently promote metastases have yet to be identified. Here we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1) abrogates the von Hippel–Lindau-mediated ubiquitination of HIF-1α, the regulatory subunit of HIF-1, and consequently promotes metastasis. The aberrant overexpression of UCHL1 facilitates distant tumour metastases in a HIF-1-dependent manner in murine models of pulmonary metastasis. Meanwhile, blockade of the UCHL1–HIF-1 axis suppresses the formation of metastatic tumours. The expression levels of UCHL1 correlate with those of HIF-1α and are strongly associated with the poor prognosis of breast and lung cancer patients. These results indicate that UCHL1 promotes metastases as a deubiquitinating enzyme for HIF-1α, which justifies exploiting it as a prognostic marker and therapeutic target of cancers.
When stabilized, HIF-1 can activate adaptation to hypoxia and metastasis. Here the authors show that upregulation of Ubiquitin C-terminal hydrolase-L1 in human cancers promotes metastasis and correlates with poor prognosis because of its role in opposing ubiquitin-mediated degradation of HIF-1.
PMCID: PMC4317501  PMID: 25615526

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