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Yoshio Miki

Publications and source records attributed to Yoshio Miki.

At least 19 recordsLinked to original sources
PubMed2006

Reduced levels of ATF-2 predispose mice to mammary tumors.

Transcription factor ATF-2 is a nuclear target of stress-activated protein kinases, such as p38, which are activated by various extracellular stresses, including UV light. Here, we show that ATF-2 plays a critical role in hypoxia- and high-cell-density-induced apoptosis and the development of mammary tumors. Compared to wild-type cells, Atf-2(-/-) mouse embryonic fibroblasts (MEFs) were more resistant to hypoxia- and anisomycin-induced apoptosis but remained equally susceptible to other stresses, including UV. Atf-2(-/-) and Atf-2(+/-) MEFs could not express a group of genes, such as Gadd45alpha, whose overexpression can induce apoptosis, in response to hypoxia. Atf-2(-/-) MEFs also had a higher saturation density than wild-type cells and expressed lower levels of Maspin, the breast cancer tumor suppressor, which is also known to enhance cellular sensitivity to apoptotic stimuli. Atf-2(-/-) MEFs underwent a lower degree of apoptosis at high cell density than wild-type cells. Atf-2(+/-) mice were highly prone to mammary tumors that expressed reduced levels of Gadd45alpha and Maspin. The ATF-2 mRNA levels in human breast cancers were lower than those in normal breast tissue. Thus, ATF-2 acts as a tumor susceptibility gene of mammary tumors, at least partly, by activating a group of target genes, including Maspin and Gadd45alpha.

Activating Transcription Factor 2↗
PubMed2006

Frequency of immunohistochemical loss of mismatch repair protein in double primary cancers of the colorectum and stomach in Japan.

PURPOSE: Colorectal cancer and gastric cancer are the two most commonly associated malignancies in Japan. We examined mismatch repair deficiency in the tumors of patients with primary colorectal and gastric cancers retrospectively. METHODS: In 103 cases and 102 healthy control subjects, surgical specimens of colorectal and gastric cancer underwent immunohistochemical analysis of mismatch repair proteins (hMLH1 and hMSH2) and microsatellite instability testing. RESULTS: Immunohistochemical and microsatellite instability testing produced similar results. High microsatellite instability in colorectal cancer was found in 23 of 103 cases (23 percent) with colorectal and gastric cancers, and in 8 of 102 healthy control subjects (8 percent). Twelve (12 percent) had mismatch repair deficiency in both colorectal and gastric cancers, and both tumors had loss of the same mismatch repair protein (hMLH1, n = 5; hMSH2, n = 7). They had the first cancer at a younger age, with a higher frequency of familial colorectal cancer than the others. Seventeen had mismatch repair deficiency in either tumor, which showed loss of expression of hMLH1. Multiple cancers and right-sided colon cancers developed more frequently in patients with mismatch repair deficiency. CONCLUSIONS: Patients with both colorectal and gastric cancers are more likely to have phenotypic evidence of hereditary nonpolyposis colorectal cancer than patients with colorectal cancer only. Among patients with double tumors, 12 percent showed a common deficiency in the same mismatch repair protein in both tumors by immunohistochemistry, and they should undergo genetic counseling for germline mutational analysis. Immunohistochemistry was effective in detecting mismatch repair deficiency of colorectal and gastric cancer as well as microsatellite instability testing, and may be more practical to perform phenotypic analysis of tumors because of its cost-effectiveness.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Accelerated growth of intestinal tumours after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC.

Mlh1-knockout mice have been developed as a useful model of hereditary non-polyposis colorectal cancer (HNPCC). In this study, we analyzed the pathology of gastrointestinal tumours (GIT) in these mice in detail and examined the possible effects of ionizing radiation on the induction of intestinal tumours to evaluate the late response to radiotherapy in HNPCC. Mlh1-/- mice spontaneously developed GIT and thymic lymphomas by 48 weeks. GIT included not only well differentiated adenocarcinomas but also poorly differentiated and mucinous adenocarcinomas, suggesting that this mouse is a good model for HNPCC. In contrast to colon cancers from HNPCC patients, however, carcinomas of Mlh1-/- mice expressed p53 and showed a lack of transforming growth factor (TGF)-betaRII mutation, which resulted in the expression of TGF-betaRII protein. Irradiation of 10-week-old Mlh1-/- mice accelerated GIT development but had little effect at 2 weeks. Mlh1+/- and Mlh1+/+ mice were not susceptible to spontaneous or radiation-induced thymic lymphomas and GIT until 72 weeks after birth. The development and pathology of GIT in Mlh1-/- mice suggest that this mouse is a good model for HNPCC, although tumour-related responsible genes might be different from HNPCC. As X-ray exposure promoted carcinogenesis of GIT in adult Mlh1-/- mice, an increased risk of secondary cancers after radiotherapy for HNPCC patients should be taken into consideration.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Protein kinase C delta activates topoisomerase IIalpha to induce apoptotic cell death in response to DNA damage.

DNA topoisomerase II is an essential nuclear enzyme that modulates DNA processes by altering the topological state of double-stranded DNA. This enzyme is required for chromosome condensation and segregation; however, the regulatory mechanism of its activation is largely unknown. Here we demonstrate that topoisomerase IIalpha is activated in response to genotoxic stress. Concomitant with the activation, the expression of topoisomerase IIalpha is increased following DNA damage. The results also demonstrate that the proapoptotic kinase protein kinase C delta (PKCdelta) interacts with topoisomerase IIalpha. This association is in an S-phase-specific manner and is required for stabilization and catalytic activation of topoisomerase IIalpha in response to DNA damage. Conversely, inhibition of PKCdelta activity attenuates DNA damage-induced activation of topoisomerase IIalpha. Finally, aberrant activation of topoisomerase IIalpha by PKCdelta is associated with induction of apoptosis upon exposure to genotoxic agents. These findings indicate that PKCdelta regulates topoisomerase IIalpha and thereby cell fate in the genotoxic stress response.

Antigens, Neoplasm↗
PubMed2006

[Gene expression profiling for prediction of response to chemotherapy].

Numerous genes whose expression is controlled by complex regulatory networks are involved in the development and progression of each cancer,and those genes will be the key factors for determining each characteristic of the tumor. The recent development of DNA microarray and related technologies provides an opportunity to perform more detailed characterization( profiling) of individual tumor cells. Indeed, the gene expression profile of a tumor provides a unique molecular portrait or signature that can be correlated with clinical behavior and drug responsiveness. The development of personalized( or customized) medicine and molecularly targeted drugs is enthusiastically awaited based on the results of research examining genomic diversity such as SNPs( single nucleotide polymorphisms), gene expression profiling with DNA microarrays, and analysis of protein expression and interactions.

Antineoplastic Agents↗
PubMed2006

Gene expression profiling of breast cancer.

Numerous genes are controlled by complex regulatory networks and involved in the development and progression of breast cancer, and these genes are the key factors determining each characteristic of the tumor. Gene expression profiling, a large scale analysis of gene expression, has created new possibilities for the molecular characterization of cancer. Systematic analysis of expression patterns of thousands of genes in tumor cells using DNA microarrays and correlation of these patterns to specific features of phenotypic variation may provide the basis for an improved taxonomy of cancer. These profiles have the potential to explain the genetic heterogeneity of breast cancer and allow treatment strategies to be planned in accordance with their probability of success in individual patients.

Antineoplastic Agents↗
PubMed2005

Protein kinase C delta regulates Ser46 phosphorylation of p53 tumor suppressor in the apoptotic response to DNA damage.

The p53 tumor suppressor is activated in the cellular response to genotoxic stress. Transactivation of p53 target genes dictates cell cycle arrest and DNA repair or induction of apoptosis; however, a molecular mechanism responsible for these distinct functions remains unclear. Recent studies revealed that phosphorylation of p53 on Ser(46) was associated with induction of p53AIP1 expression, resulting in the commitment of the cell fate into apoptotic cell death. Moreover, upon exposure to genotoxic stress, p53DINP1 was expressed and recruited a kinase(s) to p53 that specifically phosphorylated Ser(46). Here, we show that the pro-apoptotic kinase, protein kinase C delta (PKCdelta), is involved in phosphorylation of p53 on Ser(46). PKCdelta-mediated phosphorylation is required for the interaction of PKCdelta with p53. The results also demonstrate that p53DINP1 associates with PKCdelta upon exposure to genotoxic agents. Consistent with these results, PKCdelta potentiates p53-dependent apoptosis by Ser(46) phosphorylation in response to genotoxic stress. These findings indicate that PKCdelta regulates p53 to induce apoptotic cell death in the cellular response to DNA damage.

Apoptosis↗
PubMed2005

Microsatellite instability caused by hMLH1 promoter methylation increases with tumor progression in right-sided sporadic colorectal cancer.

OBJECTIVE: A subset of sporadic colorectal cancers (SCRCs) exhibits microsatellite instability (MSI). Most MSI in SCRCs is caused by hMLH1 inactivation due to promoter methylation. However, the role of MSI in the progression of SCRCs remains unclear. METHODS: Thirty-two intramucosal cancers and 63 cancers with submucosal invasion were assigned to group 1 (early-stage cancer), and 30 Dukes' B and 26 Dukes' C cancers to group 2 (advanced-stage cancer). hMLH1 promoter methylation status was determined by methylation-specific PCR. MSI was determined using five markers. hMLH1 expression was determined immunohistochemically. RESULTS: MSI was found in 1 of 95 (1.1%) tumors in group 1, compared with 4 of 56 (7.1%) tumors in group 2. In right-sided tumors, the overall frequency of hMLH1-methylation-positive tumors in group 1 was not significantly different from that in group 2 (17 of 43, 39.5%, vs. 9 of 23, 39.1%). In right-sided tumors with hMLH1 promoter methylation, the frequency of MSI-positive tumors in group 1 was significantly lower than that in group 2 (1 of 17, 5.9%, vs. 4 of 9, 44.4%, p=0.0081). CONCLUSION: The frequency of MSI caused by hMLH1 promoter methylation increases with tumor progression in right-sided SCRCs.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Enabling death by the Abl tyrosine kinase: mechanisms for nuclear shuttling of c-Abl in response to DNA damage.

c-Abl is a ubiquitously expressed tyrosine kinase that participates in a diverse array of cellular signaling cascades. The cellular response elicited by c-Abl depends upon its location in cells. Retention of c-Abl in the cytoplasm results in cell proliferation and survival. By contrast, nuclear c-Abl becomes activated and induces apoptosis following genotoxic stress. We recently demonstrated the molecular mechanisms by which c-Abl shuttles into the nucleus in response to DNA damage. In normal cells, 14-3-3 proteins sequester c-Abl in the cytoplasm. Upon exposure of cells to DNA damaging agents, JNK is activated and phosphorylates 14-3-3, resulting in the release of c-Abl into the nucleus. Importantly, nuclear targeting of c-Abl is required for the induction of apoptosis in response to DNA damage. Thus, c-Abl may function in determining cell fate via its subcellular localization. In this review, we focus on the implications of these findings on our understanding of Abl-regulated cellular functions and on potential therapeutic strategies to manipulate the aberrant kinase.

Active Transport, Cell Nucleus↗
PubMed2005

JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage.

The ubiquitously expressed c-Abl tyrosine kinase localizes to the cytoplasm and nucleus. Nuclear c-Abl is activated by diverse genotoxic agents and induces apoptosis; however, the mechanisms that are responsible for nuclear targeting of c-Abl remain unclear. Here, we show that cytoplasmic c-Abl is targeted to the nucleus in the DNA damage response. The results show that c-Abl is sequestered into the cytoplasm by binding to 14-3-3 proteins. Phosphorylation of c-Abl on Thr 735 functions as a site for direct binding to 14-3-3 proteins. We also show that, in response to DNA damage, activation of the c-Jun N-terminal kinase (Jnk) induces phosphorylation of 14-3-3 proteins and their release from c-Abl. Together with these results, expression of an unphosphorylated 14-3-3 mutant attenuates DNA-damage-induced nuclear import of c-Abl and apoptosis. These findings indicate that 14-3-3 proteins are pivotal regulators of intracellular c-Abl localization and of the apoptotic response to genotoxic stress.

14-3-3 Proteins↗
PubMed2005

Postoperative prognosis of node-negative breast cancers predicted by gene-expression profiling on a cDNA microarray of 25,344 genes.

BACKGROUND: In Japan, postoperative relapse occurs within five years in 9.2 to 16% of patients whose breast cancers have not metastasized to lymph nodes at the time of initial surgery(node-negative, n0). Attempts to find molecular markers able to classify n0 breast cancers in terms of postoperative prognosis have not been successful. METHODS: To identify molecular indicators of prognosis for this type of cancer, we used a cDNA microarray consisting of 25,344 human genes to investigate expression profiles of 12 primary breast cancers from patients whose tumors recurred within five years after surgery(5Y-R) and 12 from patients who survived disease-free for more than five years (5Y-F). RESULTS: Sets of genes characterizing each group in terms of expression patterns in the tumors were selected by Mann-Whitney and random-permutation tests: these panels included 21 genes expressed highly in 5Y-R tumors than in 5Y-F tumors, and 37 with higher expression in the 5Y-F group than in the 5Y-R group. CONCLUSIONS: We established a scoring system to prediction of postoperative prognosis which was 100% accurate as to the actual clinical outcomes of the 24 cases and therefore might be useful for predicting prognosis of n0 breast cancers in a clinical setting. The prognostic score system clearly separated the two groups without any overlap, and accurately predicted prognosis in 6 additional cases. Moreover, the extensive list of tumor-related genes identified in these experiments provides valuable information about progression of breast cancer and suggests potential target molecules for therapy of n0 breast cancers.

Adult↗
PubMed2005

[Clinical genetics for hereditary cancers: from the viewpoint of physicians working at a hospital specialized in cancer].

In our daily practice, we provide clinical genetic consultation for patients at risk for hereditary cancers. The clinical characteristics of hereditary cancer syndromes in adults differ from those of hereditary diseases in children, although both involve genetic disease. One major difference is the difficulty in diagnosing hereditary cancers. Genetic testing has enabled us to diagnose HNPCC and familial breast and ovarian cancers. Another difference is the possibility to improve the outcomes of hereditary cancer syndromes by medical intervention. Intentional surveillance thus plays a key role in the management of hereditary cancer syndromes. These features make genetic counseling essential for hereditary cancer syndromes, including genetic testing and lifelong disease management. Networking among genetic disease specialists is particularly necessary. Clinical geneticists should be responsible for not only genetic disease but also for genomic information about cancer, with the ultimate goal of providing "order-made" medical consultation and services. Another important goal is the establishment of systems for the comprehensive care of patients and for the career development of specialists to provide regional-based care for persons who have or are at risk for hereditary cancers, including future generations.

Adult↗
PubMed2005

[Gene testing of hereditary cancer on comprehensive gene medical examination support system].

It has been estimated that genetic factors or a combination of genetic and environmental factors play a role in the development of 10-15% of all cancers. A genetic cause of hereditary cancer has been identified in more than 40 diseases till now. For preventing this cancer, gene testing is essential because it has no definite clinical marker as in hereditary non-polyposis colorectal cancer: HNPCC. Much more experience must be accumulated in this testing at the clinical base in order to increase specificity and sensitivity while safeguarding ethical, legal and social issues (ELSI). Recently, the Personal Information Protection Law was enforced. Gene inspection involving hereditary cancer should be carried out under a comprehensive gene medical examination organization. It is important for the family doctor, medical specialist, and gene inspection person in charge to cooperate closely with one another, and this will be a subject of future study.

Adenomatous Polyposis Coli↗
PubMed2005

[SNPs associated with adverse effects].

In recent years, pharmacogenomics have received much attention from the increased expectations for so-called order-made medicine. It is experientially clear that inter-individual differences exist in the degree of efficacy and occurrence of adverse effects. These inter-individual differences are observed not only among anticancer chemotherapeutics but in almost all drugs. Several studies have revealed that genetic factors are involved in these inter-individual differences. To date, the relationships have been revealed between adverse effects of some anticancer drugs and polymorphisms of drug metabolizing genes. Such relationships include 5-FU and DPYD gene, methotorexate and MTHFR gene, irinotecan and UGT 1A1 gene and 6-MP and TPMT gene. By using information on these polymorphisms, it will be possible to predict the occurrence of adverse effects before using anticancer drugs. In particular, information on polymorphisms related to the possibly adverse effects of irinotecan is now given in its package leaflet. This means that order-made medicine is a step closer. In this review, we discuss the relationships between polymorphisms of genes and the adverse effects of anticancer drugs. Furthermore, we want to suggest the direction of further pharmacogenomic studies with an eye to the realization of order-made medicine.

Antineoplastic Agents↗
PubMed2004

Gene expression patterns as marker for 5-year postoperative prognosis of primary breast cancers.

PURPOSE: To establish the novel prognostic markers for breast cancer, gene expression profile was examined genome-wide. METHODS: We used cDNA microarray consisting of 18,432 human genes to compare genome-wide expression profiles of eight primary breast cancers, four from patients who died of breast cancer within 5 years after surgery (5D group) and four who survived disease-free for more than 5 years (5S group). RESULTS: We identified 21 genes whose expression was greater in tumors from the 5D group than in 5S tumors, and 23 with higher expression in the 5S group than in the 5D group. We established a Prognostic Index (PI) for prediction of postoperative prognosis, based on the aberrant expression profiles of ten of those genes. Among 20 additional cases chosen blindly, ten presented with high prognostic scores (>7, good) according to the PI; the remaining ten cases revealed scores <7 (poor). The PI predicted the actual 5-year clinical outcomes of these 20 cases with 100% accuracy. CONCLUSION: Our PI system is reliable in clinical settings for predicting postoperative risk for breast cancer. The extensive list of genes provides valuable information about progression of breast cancer and suggests potential target molecules for treating this disease.

Adult↗
PubMed2004

Familial breast and ovarian cancers.

About 60% of familial breast and ovarian cancers in Japan involve germline mutations of the BRCA1 or BRCA2 ( BRCA1/2) genes. These genes contribute to genetic stability and DNA repair and act as tumor suppressor genes. Mutation analysis of the BRCA1/2 genes has improved our understanding of both common mutation patterns in Japanese patients and the clinicopathological features of BRCA1/2-related cancers. BRCA1-related breast cancers are characterized by poor prognosis, a low rate of estrogen receptor positivity, and histological predominance of solid-tubular carcinoma. BRCA1-related ovarian cancers are associated with a high frequency of serous adenocarcinoma and a good outcome. Further large-scale studies are needed to delineate genotype-phenotype relations and penetrance in BRCA1/2-related breast and ovarian cancers in Japan. The development of systems for clinical genetics in Japan, including genetic counseling, has led to the increased use of genetic testing for the clinical management of BRCA1/2-related cancers. Three options are available for carriers of BRCA1/2 mutations: intensive surveillance, chemoprevention, and prophylactic surgery. Studies done in other countries indicate that prophylactic surgery effectively prevents the development of breast and ovarian cancers in carriers of BRCA1/2 mutations. However, prophylactic mastectomy remains controversial in Japan, and now systematic intensive surveillance is generally performed for the prevention of breast cancer in women at high risk. Early detection of ovarian cancer remains challenging, resulting in increased acceptance of the need for prophylactic oophorectomy in women at risk. This review summarizes experimental and clinical findings about familial breast and ovarian cancers, including data on Japanese patients.

Adenocarcinoma↗
PubMed2004

Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage.

BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2 are tumor suppressor genes, the mutant phenotypes of which predispose to breast and ovarian cancers. Intensive research has shown that BRCA proteins are involved in a multitude of pivotal cellular processes. In particular, both genes contribute to DNA repair and transcriptional regulation in response to DNA damage. Recent studies suggest that BRCA proteins are required for maintenance of chromosomal stability, thereby protecting the genome from damage. New data also show that BRCAs transcriptionally regulate some genes involved in DNA repair, the cell cycle, and apoptosis. Many of these functions are mediated by a large number of cellular proteins that interact with BRCAs. The functions of BRCA proteins are also linked to distinct and specific phosphorylation events; however, the extent to which phosphorylation-activated molecular pathways contribute to tumor suppressor activity remains unclear. Finally, the reasons why mutations in BRCA genes lead to the development of breast and ovarian cancers are not clearly understood. Elucidation of the precise molecular functions of BRCAs is expected to improve our understanding of hereditary as well as sporadic mammary carcinogenesis.

Apoptosis↗