Hirotaka Koizumi

St. Marianna University School of Medicine, Kawasaki Si, Kanagawa, Japan

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Publications (50)146.85 Total impact

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    ABSTRACT: Increased serum carcinoembryonic antigen (CEA) levels have been associated with a poor outcome in lung cancer. The aim of this study was to further clarify the associations between CEA levels and adenocarcinoma subtypes.
    No preview · Article · Dec 2015 · Cancer Treatment Communications
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    ABSTRACT: In recent papers, Ki67 labeling index (LI) has been used to classify breast cancer patients into the low and high Ki67LI groups for comparison studies, which showed significant differences in many prognostic factors. It has not been clarified whether image analysis software can be used for calculating LI in breast cancer. In our study, we examined whether Ki67LI in breast cancer calculated using image analysis software correlates with that measured on the basis of visual. Fifty patients were randomly selected among breast cancer patients who underwent surgical operation from March, 2010 to May, 2010 in our hospital without preoperative chemotherapy. In this study, for the virtual slide system (VSS: VS120-L100, Olympus, Tokyo, Japan), the high-resolution VSs of all the 50 patients were prepared as samples. The image analysis software use for calculating LI was Tissuemorph Digital Pathology (Tissuemorph DP: Visiopharm, Hoersholm, Denmark). The calculated LI was extracted from 3 to 5 views containing hot spots. The LI calculated using Tissuemorph DP was designed as LI/image/T. The digital image of 3 to 5 LI/image/T views was printed out, and on the digital photograph, we counted visually the number of Ki67-immunopositive cells in exactly the same area, and the percentage of Ki67-immunopositive cells was designed as LI/direct. Moreover, a pathologist's assistant (PA) determined the tumor area in the same specimen using VSS and calculated LI using Tissuemorph DP, which was designed as LI/image/PA. The chief pathologist (CP) similarly calculated LI which was designed as LI/image/CP. We evaluated the degree of agreement between different data sets "LI/image/T and LI/direct" and "LI/image/T, LI/image/CP, and LI/image/PA" by using interclass correlation coefficient (ICC). The average counts of cells were as follows: LI/direct, 3209.7 ± 1970.4 (SD); LI/image/T, 2601.6 ± 1697.1; LI/image/PA, 2886.5 ± 2027.5; LI/image/CP, 18805.5 ± 22293.4. The values of LI/direct and LI/image/T showed almost perfect agreement as showed by an ICC of 0.885 (95 % CI, 0.806-0.933; p < 0.001). The agreement among three investigators was almost perfect. The obtained ICC was 0.825 (95 % CI, 0.739-0.890; p < 0.001) among the data of LI/image/T, LI/image/CP and LI/image/PA. There were five cases that immunopositivity for Ki67 showed a more than 10 % disagreement between LI/direct and LI/image/T. The merits of calculating Ki67 LI using Tissuemorph DP are as follows. First, the staining intensity of the cells to be counted can be adjusted. Second, the portion of a tumor including "hot spots" for counting can be chosen. Third, many cancer cells can be counted more rapidly using Tissuemorph DP than by visual observation. However, it is important that pathologist should check and carry out the final decision of the data, when Ki67 LI using Tissuemorph DP is calculated.
    No preview · Article · Aug 2015 · Breast Cancer
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    ABSTRACT: Malignant melanoma (MM), an aggressive skin neoplasm, can be difficult to differentiate histologically from benign melanocytic nevi (BMN). Although immunohistochemical analysis could facilitate diagnosis of MM, markers that discriminate between benign and malignant lesions have not yet been established. However, CD10 expression is associated with MM progression. We immunostained 36 MM and 50 BMN specimens for CD10 to evaluate whether CD10 immunostaining could distinguish between BMN and MM tumors. In the 36 MM samples, we found CD10 expression in 17 (47.2%) sample tumor cells and 32 (88.9%) stromal cells, for 34 of the 36 MM specimens (94.4%) overall. In contrast, no BMN (0/50) samples had CD10+ tumor cells, although a few (8/50, 16.0%) showed stromal staining. The two specimen types thus significantly differed in CD10 expression (P<0.01), indicating that melanocytic CD10+ tumor cells are likely to be malignant. Also, melanocytic stromal cells with diffuse, strong CD10 expression are more likely to be malignant than those with light, focal CD10 expression. Although hematoxylin and eosin staining is fundamental to the diagnosis of melanocytic lesions, CD10 immunostaining may help distinguish between BMN and MM.
    Preview · Article · Jan 2015
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    ABSTRACT: Objective: An important cause of liver re-metastasis from colon cancer is remnant micrometastasis (MiM). MiM is a miniscule metastatic lesion that results from hematogenous spread of tumor cells along with or after the original metastasis from colon to liver. Thus, an adequate surgical margin is necessary to lower a patient’s risk of relapse. Questions have arisen whether the guideline 1-cm surgical margin can be reduced in cases in which neoadjuvant chemotherapy (NAC) has been performed. We conducted a histopathologic study to determine the appropriate hepatectomy margin in such cases.Methods: We studied 76 cases of colorectal liver metastasis treated between January 2005 and December 2013 at St. Marianna University School of Medicine Hospital. NAC had been performed in 35 of these cases. We evaluated patients’ sex; age; site, clinical stage, and histologic type of the primary tumor, clinical and histologic effects of the NAC, histologic characteristics and size of the hepatic macrometastasis, number of cases in which MiM was found and the number of MiMs per case, histologic characteristics and size of the MiM(s), distance from the macrometastasis to the MiM, and exact location of the MiM(s) and tested between-group differences in these variables statistically. We also tested correlation between size of the macrometastasis and both distance between the macrometastasis and MiM and the number of MiMs per case.Results: Positive, but non-significant, correlation was found between size of the macrometastasis and both distance between the macrometastasis and MiM and the number of MiMs per case. Regardless of whether NAC was performed, most MiMs we examined were within 5 mm of the macrometastasis, but some were within 9 mm.Conclusion: Our data indicate that, regardless of whether NAC is performed before hepatectomy for liver metastasis from colorectal cancer, a minimum 1-cm surgical margin is necessary to ensure inclusion of micrometastases.
    Preview · Article · Jan 2015
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    ABSTRACT: Cardiac metastasis from colorectal cancer is rare. Such metastasis is usually discovered during autopsy; antemortem diagnosis is rare. A 76-year-old woman in whom we had performed right hemicolectomy for ascending colon cancer was noted to have elevated tumor markers during a follow-up examination 4 months after the surgery. Chest CT indicated a cardiac tumor that was approximately 6 cm in diameter, and we suspected a metastatic cardiac tumor. Subsequently, obstructive jaundice developed as a result of lymph node metastases around an extrahepatic bile duct, and a stent was placed. The patient refused aggressive treatment and was simply followed up clinically. Within 2 months, the cardiac tumor enlarged enough to cause cardiac failure, and death ensued 7 months after the surgery. Autopsy revealed a myocardial tumor, approximately 7 x 5 cm, that extended from the right atrium to the right ventricle. The histopathologic diagnosis was cardiac metastasis from ascending colon cancer. We describe in detail this case of rapidly progressive cardiac metastasis that was discovered after surgical treatment of ascending colon cancer. In searching the medical literature, we found only 14 cases of metastasis of colorectal cancer to the heart. We describe our case in detail and review our experience in light of the available literature.
    Preview · Article · Jan 2015
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    ABSTRACT: With widespread use of proton pump inhibitors (PPIs) has come characteristic gastric mucosal changes such as parietal cell protrusions (PCPs) and so-called fundic gland polyps (FGPs). Nevertheless, whether these lesions are actually PPI-related gastric mucosal lesions has not been fully clarified. The present study focused on this issue. We firstly examined the purported relation between the emergence of PCPs and PPI use. We also investigated the relation between PPI use and the emergence of cystically dilated glands (CDGs) that can give rise to elevated mucosal lesions such as FGPs. In addition, we performed histopathologic and immunohistochemical analyses to clarify the characteristics of PCPs and PCP-affected gastric oxyntic mucosa. A significant relation between the emergence of PCPs and PPI use was confirmed. In contrast, no significant relation was found between the emergence of CDGs and PPI use. Histologic and immunohistochemical analyses showed PCPs to be hyperplastic lesions. In the PCP-affected oxyntic mucosa, the isthmus-and-neck region of the fundic glands was elongated and the base region was shortened in relation to the total mucosal thickness. These changes were accompanied by an increase in the number of parietal cells and a decrease in the number of chief cells. Immunohistochemical analysis suggested impairment of both parietal cell differentiation and mucous neck-to-chief cell differentiation.Furthermore, our study reinforced the notion that elevated hydrostatic pressure and cytoplasmic edema due to movement of water from interstitial space toward the lumen of oxyntic glands via parietal cells give rise to the formation of PCPs, oxyntic dilatation, and CDGs. The detailed mechanism of PCP formation and its clinical implications are expected to be clarified in future studies.
    Preview · Article · Jan 2015
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    ABSTRACT: Correlations between maximum standardized uptake value (SUVmax) in fluorodeoxyglucose positron emission tomography (FDG-PET) and IASLC/ATS/ERS histopathologic subtypes of lung adenocarcinoma remain unclear. Therefore, the aim of this study was to retrospectively clarify associations between SUVmax and adenocarcinoma subtypes with postoperative outcomes. Associations of SUVmax measured in preoperative FDG-PET/CT and histologic subtypes of lung adenocarcinoma resected in our hospital were analyzed retrospectively. Overall and disease-free survival rates after surgery were calculated by the Kaplan-Meier method, and survival differences between patient groups were tested by the log-rank test. Multivariate analysis for survival was performed using the Cox regression model. A total of 255 patients (130 men and 125 women; mean age, 69 years; range, 22-88 years) were included in the study. Clinical stages included IA in 151 patients, IB in 79, IIA in 9, IIB in 10, and IIIA in 6. SUVmax was closely associated with histologic subtype in resected specimens (p<0.0001). Values were highest in micropapillary predominant invasive adenocarcinoma (MPA) followed by solid predominant (SPA), invasive mucinous (IMA), acinar predominant (APA), papillary predominant (PPA), lepidic predominant (LPA), minimally invasive adenocarcinoma (MIA), and adenocarcinoma in situ (AIS). When the subtypes were classified into three subgroups [group A, AIS+MIA+LPA (low risk); group B, APA+PPA+IMA (intermediate risk); and group C, SPA+MPP (high risk)] by expected postoperative prognoses, there were significant differences in SUVmax among the subgroups corresponding to recurrence risk (p=0.0001). Preoperative SUVmax was closely associated with both adenocarcinoma subtype and aggregated subgroups, reflecting malignant grade of the tumor and prognosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Nov 2014 · Lung cancer (Amsterdam, Netherlands)
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    ABSTRACT: Background: The relationships between the subtypes defined by the new international histologic classification of lung adenocarcinoma (IASLC/ATS/ERS) and epidermal growth factor receptor (EGFR) mutations were studied. Patients and methods: We retrospectively reviewed 320 patients with lung adenocarcinoma (162 women, 158 men; mean age, 69 years) who had undergone complete resection, focusing on the new histologic subtypes and EGFR mutations. The clinical stage was IA in 196 patients, IB in 95, IIA in 10, IIB in 10, IIIA in 6, and IV in 3. Results: The most prevalent subtype was papillary (35.0%), followed by acinar (29.4%), lepidic (13.1%), solid (7.2%), adenocarcinoma in situ (6.6%), minimally invasive adenocarcinoma (6.3%), micropapillary (1.6%), and invasive mucinous adenocarcinoma (1.0%). These subtypes were predictive for both postoperative disease-free and overall survival. EGFR mutations, detected in 40.6% of all cases, were most frequent in acinar (48.4%), followed by minimally invasive adenocarcinoma (45.0%) and papillary (43.8%). They were least frequent in the solid subtype (17.4%). EGFR mutation status did not affect postoperative disease-free or overall survival. Conclusion: The outcome after complete resection for lung adenocarcinoma was predicted by the proposed subtype classification. Because EGFR mutations were found in all subtypes, mutation analyses are essential to identify patients with postoperative relapse who would benefit from EGFR-tyrosine kinase inhibitor therapy.
    No preview · Article · Oct 2014 · Clinical Lung Cancer
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    ABSTRACT: Some reports suggest that the rate of definitive diagnosis of malignant tumors, namely, the final diagnosis being revised to a higher stage, in patients diagnosed as having flat epithelial atypia (FEA) by percutaneous needle biopsy of the breast (PNB) is as low as 0-3 %. However, other reports suggest that the rate is as high as 10 % or more, bringing confusion on this issue. We examined the positive predictive value for malignancy in the patients diagnosed as having pure FEA and the patients' radiolopathological characteristics observed in our hospital. Of the patients who underwent PNB in our facility, those who were diagnosed as having pure FEA were recruited as the subjects of this study. Of the 4,197 consecutive patients who underwent PNB, 44 (1.0 %) were diagnosed as having pure FEA following a re-examination. Among 44 cases, 39 cases were selected as the subjects of this study. Among the 39 patients, six patients were diagnosed as having malignant lesions, two of whom had invasive carcinoma of no special type (papillotubular type), one had tubular carcinoma, one had ductal carcinoma in situ (DCIS) of high nuclear grade, one had DCIS of intermediate nuclear grade, and one had DCIS of low nuclear grade. The diameters of 6 malignant lesions were 10-30 mm at ultrasonography (US) examination. Five of the 39 patients had contralateral breast cancer. The positive predictive value for malignancy of pure FEA was 15.7 %. The patients with pure FEA may make a follow up without an excisional biopsy when the lesion sizes less than 10 mm on US examination.
    No preview · Article · Apr 2014 · Breast Cancer
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    ABSTRACT: Brain metastases of gynecological malignancies are rare, but the incidence is increasing. Patients with brain metastases have a poor prognosis, therefore early detection and optimal management is necessary. In order to determine a new biomarker, we aimed to identify proteins that associated with brain metastases. We investigated proteins associated with brain metastases of gynecological malignancies in three patients who underwent surgical resection (stage IIb cervical cancer, stage Ib endometrial cancer, and stage IIIb ovarian cancer). Proteomic analysis was performed on formalin-fixed paraffin-embedded (FFPE) samples of the primary tumors and brain metastases, which were analyzed by liquid chromatography with tandem mass spectrometry. Thereafter, candidate proteins were identified by the Scaffold system and Mascot search program, and were analyzed using western blotting and immunohistochemistry. As a result, a total of 129 proteins were identified. In endometrial and ovarian cancers, western blotting revealed that the expression of alpha-enolase (ENO1) and triosephosphate isomerase (TPI-1) was higher and the expression of Transgelin-2 (TAGLN2) was lower in metastatic tumors than in primary tumors. On the other hand, the expression of TPI-1 and TAGLN2 was lower in metastatic tumors than in primary tumors in cervical cancer. Immunohistochemistry confirmed that ENO1 expression was elevated in the metastatic tumors compared with the primary tumors. In conclusion, the present study showed that FFPE tissue-based proteomics analysis can be powerful tool, and these findings suggested that ENO1, TPI-1, and TAGLN2 may have a role in the development and progression of brain metastasis from gynecological malignancies.
    Full-text · Article · Mar 2013 · Human Cell
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    ABSTRACT: Sessile serrated adenoma/polyps (SSA/Ps) of the colon are thought to be precursors of sporadic carcinomas. Although it is suggested that SSA/P may grow rapidly from the early stage, its cell kinetics remains obscure. To solve this problem, we analyzed the mitotic and apoptotic activity of normal crypts, microvesicular hyperplastic polyps (MVHPs), and tubular adenomas (TAs), using phospho-histone H3 and cleaved caspase 3 immunohistochemistry. The mitotic index for SSA/Ps (mean, 5.63) and TAs (6.98) was significantly higher than those for normal crypts (2.72) and MVHPs (2.86). Of all tested lesions, the apoptotic index was lowest for SSA/Ps (0.96; normal, 2.71; MVHPs, 2.62; TAs, 6.01) with statistically significant differences. The net growth ratio was close to 1.0 in normal crypts (1.07) while remaining low in MVHPs (1.06) and TAs (1.38), but was markedly elevated in SSA/Ps (7.32, P < 0.01) due to the large imbalance between mitosis and apoptosis. As to apoptosis regulatory proteins, expression of anti-apoptotic Bcl-2 was significantly reduced or undetectable in MVHPs and SSA/Ps, while TAs showed stronger staining than normal crypts. Expression of pro-apoptotic Bax and its activators, Bim and Bad, was significantly reduced in MVHPs and SSA/Ps. We suggest that other complex mechanisms may act synergistically with Bax, Bim, or Bad deficiency to regulate apoptosis suppression in SSA/Ps.
    Full-text · Article · Jan 2013 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
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    ABSTRACT: A case of a glomus tumor originating from the lung is reported. A 43-year-old female had undergone resection of a right lung tumor following a clinical diagnosis of carcinoid, sclerosing hemangioma, or other sarcoma. Histologically, the tumor comprised uniform small round to oval cells with centrally located nucleus, a clear cytoplasm, and apparent cell borders. The tumor also showed a focally hemangiopericytomatous pattern with irregularly branching or dilated vessels. Electron microscopy revealed smooth muscle differentiation of the tumor cells. Immunostaining further revealed that the tumor cells expressed smooth muscle actin, h-caldesmon, muscle specific actin (HHF-35), but not cytokeratin, epithelial membrane antigen, synaptophysin, or chromogranin A. Based on these findings, a diagnosis of primary pulmonary glomus tumor was established. Glomus tumors of the lung are very rare and only 21 cases have been reported to date. The histological features of the present tumor and the relevant literature are discussed.
    Preview · Article · Sep 2012
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    ABSTRACT: Malignant mesothelioma (MM) is a rare disease with a poor prognosis. Pleural mesothelioma, which is the most common type of MM, is considered to be caused by asbestos exposure and is increasing in incidence, with about 15,000 new cases diagnosed worldwide annually. On the other hand, peritoneal mesothelioma is a very rare type of MM; thus, its pathogenesis is even less understood than pleural mesothelioma. Recent research on the pathogenesis of malignant pleural mesothelioma has indicated that both epigenetic and genetic alterations contribute to tumorigenesis. Here, we hypothesize that peritoneal mesothelioma also has an epigenetic alteration in the same genes (Kazal-type serine peptidase inhibitor domain 1 (KAZALD1), transmembrane protein 30B (TMEM30B), and mitogen-activated protein kinase 13 (MAPK13)). Our goal is to identify DNA methylation of these three candidate genes in two peritoneal mesothelioma cases. Laser capture microdissection was used to separate diseased sections of formalin-fixed paraffin-embedded samples from one surgically resected tissue (epithelial type) and one autopsy tissue (sarcomatous type). Genomic DNA was subsequently extracted by the standard phenol chloroform method. The DNA was then treated with sodium bisulphite, and pyrosequencing analysis was used to quantitatively analyze the methylation of candidate genes reported to be hypermethylated in malignant pleural mesothelioma (KAZALD1, TMEM30B, and MAPK13). TMEM30B and MAPK13 were not methylated in either case. However, KAZALD1 was highly methylated in sarcomatoid-type peritoneal mesothelioma. We first report that the KAZALD1 gene was hypermethylated in sarcomatoid-type malignant peritoneal mesothelioma.
    Full-text · Article · Jul 2012 · Tumor Biology
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    ABSTRACT: Heat shock protein 27 (hsp27) is expressed by squamous cell carcinoma of the uterine cervix. Results from an earlier study by our group indicted that hsp27 may be a diagnostic marker for cervical intraepithelial neoplasia (CIN) and carcinoma. p16 expression is known to be elevated in intraepithelial uterine cervical cancer and grades 2 and 3 lesions (CIN2, CIN3), but has also been reported to be negative in 5-20% of cervical cancer and CIN lesions. The aim of our study was to confirm immunohistochemically the expression of hsp27 and p16 in cervical lesions. Formalin-fixed, paraffin-embedded cervical tissue specimens obtained between 2002 and 2010 were investigated for hsp27 and p16 expression. Positive staining was detected for hsp27 in 63% of normal cervical tissues, 47% of CIN1 lesions, 75% of CIN2 lesions, 92% of CIN3 lesions, and 100% of squamous cell carcinomas (SCC); the corresponding rates for p16 positivity were 29, 47, 67, 92, and 75%, respectively. Positive staining for both hsp27 and p16 was observed in 6% of normal cervical tissues and in 19% of CIN1, 18% of CIN2, 85% of CIN3, and 75% of SCC specimens. Hsp27 or p16 positivity had a sensitivity of 95.6 or 84.7% and a specificity of 37.2 or 70.5%, respectively, for the identification of CIN3 or SCC lesions; when both hsp27 and p16 were assessed, both the sensitivity and specificity were improved. In conclusion, both hsp27 and p16 immunohistochemistry is a useful tool for the diagnosis of CIN3 lesions or cervical SCC.
    No preview · Article · Feb 2012 · Human Cell
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    ABSTRACT: The breast cancer suppressor BRCA1 forms a stable heterodimeric E3 ubiquitin ligase with BARD1. Each protein controls the abundance and stability of the other, and loss of the interaction leads to BRCA1 degradation. Here, we show that HERC2, a protein recently implicated in DNA damage repair, targets BARD1-uncoupled BRCA1 for degradation. HERC2 shuttles between the nucleus and the cytoplasm. Its COOH-terminal HECT-containing domain interacts with an NH(2)-terminal degron domain in BRCA1. HERC2 ubiquitinates BRCA1; this reaction depends on Cys(4762) of HERC2, the catalytic ubiquitin binding site, and the degron of BRCA1. The HERC2-BRCA1 interaction is maximal during the S phase of the cell cycle and rapidly diminishes as cells enter G(2)-M, inversely correlated with the steady-state level of BRCA1. Significantly, HERC2 depletion antagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G(2)-M checkpoint activity. Conversely, BARD1 protects BRCA1 from HERC2-mediated ubiquitination. Collectively, our findings identify a function for HERC2 in regulating BRCA1 stability in opposition to BARD1. The HERC2 expression in breast epithelial cells and breast carcinomas suggests that this mechanism may play a role in breast carcinogenesis.
    Preview · Article · Aug 2010 · Cancer Research
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    ABSTRACT: Various agents used in breast cancer chemotherapy provoke DNA double-strand breaks (DSBs). DSB repair competence determines the sensitivity of cells to these agents whereby aberrations in the repair machinery leads to apoptosis. Proteins required for this pathway can be detected as nuclear foci at sites of DNA damage when the pathway is intact. Here we investigate whether focus formation of repair proteins can predict chemosensitivity of breast cancer. Core needle biopsy specimens were obtained from sixty cases of primary breast cancer before and 18-24 hours after the first cycle of neoadjuvant epirubicin plus cyclophosphamide (EC) treatment. Nuclear focus formation of DNA damage repair proteins was immunohistochemically analyzed and compared with tumor response to chemotherapy. EC treatment induced nuclear foci of gammaH2AX, conjugated ubiquitin, and Rad51 in a substantial amount of cases. In contrast, BRCA1 foci were observed before treatment in the majority of the cases and only decreased after EC in thirteen cases. The presence of BRCA1-, gammaH2AX-, or Rad51-foci before treatment or the presence of Rad51-foci after treatment was inversely correlated with tumor response to chemotherapy. DNA damage response (DDR) competence was further evaluated by considering all four repair indicators together. A high DDR score significantly correlated with low tumor response to EC and EC + docetaxel whereas other clinicopathological factors analyzed did not. High performing DDR focus formation resulted in tumor resistance to DNA damage-inducing chemotherapy. Our results suggested an importance of evaluation of DDR competence to predict breast cancer chemosensitivity, and merits further studying into its usefulness in exclusion of non-responder patients.
    Full-text · Article · Mar 2010 · Breast cancer research: BCR
  • Akiko Ono · Hirotaka Koizumi

    No preview · Article · Nov 2009 · Human Pathlogy
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    ABSTRACT: Gene-expression profiling classified breast cancer to intrinsic subtypes, including luminal A and B, HER2 positive, normal-breast-like, and basal-like tumors. Of these, basal-like tumors that express basal cytokeratins and that are negative for estrogen receptor alpha, progesterone receptor, and HER2 show the most aggressive phenotype with a poor prognosis. Analyses of clinical samples and basic research indicate that basal-like breast cancer is caused by deficiencies in the breast cancer susceptibility protein, BRCA1. Indeed, conditionally deleting BRCA1 from the mammary gland causes mice to develop basal-like cancers at high rates. One of the major functions of BRCA1 is DNA double-strand break (DSB) repair, and its failure to perform causes increased sensitivity of cells to DNA damage-inducing agents, such as PARP inhibitors, DNA cross-linkers, or topoisomerase inhibitors. Therefore, BRCA1 dysfunction could be a principal target for therapeutic application of basal-like breast cancer. Recently, significant progress has been made in understanding the BRCA1 cascade in response to DSBs, where ubiquitin polymer formation plays critical roles. Ubiquitination was indeed found to be an apparent early response of breast cancer to neoadjuvant treatment with epirubicin and cyclophosphamide. Deducing the role of BRCA1 ubiquitin E3 ligase activity in this pathway is a critical challenge to further clarify its functional mechanism. In individualized treatment of breast cancer, evaluation of the DNA repair capacity by the BRCA1 pathway may be an important issue when determining proper treatment of basal-like breast cancer.
    No preview · Article · Jun 2009 · Breast Cancer
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    ABSTRACT: Proteomic analysis of squamous cell carcinoma of the uterine cervix was performed using total protein from archival formalin-fixed, paraffin-embedded tissues. A wide range of proteins with molecular weights of 10 to greater than 200 kd was extracted from formalin-fixed, paraffin-embedded tissues using a recently developed protocol based on the heat-induced antigen retrieval technique. The extracted proteins from normal squamous epithelium (n = 53) and squamous cell carcinoma (n = 21) were fluorescently labeled and separated using 2-dimensional gel electrophoresis. We identified 728 differentially expressed proteins, with 144 up-regulated and 584 down-regulated as compared with normal squamous epithelial tissue samples. Nine proteins showing pronounced up-regulation in squamous cell carcinoma were analyzed on liquid chromatography-tandem mass spectrometry. Among the candidate proteins identified, minichromosome maintenance 8, a disintegrin and metalloproteinase domain 18, and heat shock protein 27 were analyzed in Western blotting, resulting in significant overexpression of heat shock protein 27 in squamous cell carcinoma over normal mucosa (P < .05). Furthermore, immunostaining revealed heat shock protein 27 overexpression not only in squamous cell carcinoma but in various stages of cervical intraepithelial neoplasia (grades 1-3, n = 90), including dysplasia and carcinoma in situ. The expression levels of heat shock protein 27 in cervical intraepithelial neoplasia grades 1 to 3 and squamous cell carcinoma were significantly higher than that in normal mucosa (P < .05). In the neoplastic lesions, heat shock protein 27 expression levels in cervical intraepithelial neoplasia grade 3 and squamous cell carcinoma were significantly higher than that in cervical intraepithelial neoplasia grade 1 (P < .05). These results may suggest a role of heat shock protein 27 in tumor development and progression in the cervical intraepithelial neoplasia-squamous cell carcinoma sequence. Future experiments using formalin-fixed, paraffin-embedded tissue-based proteomic analysis will be a powerful tool for various pathologic studies.
    No preview · Article · Sep 2008 · Human pathology

  • No preview · Article · Jan 2008

Publication Stats

1k Citations
146.85 Total Impact Points

Institutions

  • 1995-2015
    • St. Marianna University School of Medicine
      • • Department of Pathology
      • • Department of Obstetrics and Gynecology
      • • Department of Surgery
      • • Department of Medicine
      Kawasaki Si, Kanagawa, Japan
  • 1991
    • National Center of Neurology and Psychiatry
      • Department of Neuromuscular Research
      Кодаиры, Tōkyō, Japan