Human endoplasmic reticulum oxidoreductin 1‐α (hERO1‐α) is an oxidizing enzyme that exists in the endoplasmic reticulum and its expression is augmented under hypoxia. It regulates a redox state of ...various kinds of protein through reoxidation of “client” protein disulfide isomerase. Interestingly, although the expression of hERO1‐α in normal tissues was comparatively limited, various types of cancer cells expressed it in large amounts. Therefore, we examined the role of ERO1‐α in tumor growth using murine breast cancer line 4T1 and found that knockdown of murine ERO1‐α inhibited in vivo tumor growth and decreased lung metastasis compared with wild‐type 4T1. Moreover, we investigated the relationship between expression of hERO1‐α and prognosis in breast cancer patients. Seventy‐one patients with breast cancer who underwent surgery between 2005 and 2006 in Sapporo Medical University Hospital (Sapporo, Japan) were analyzed in this study. Significant differences were found between the hERO1‐α‐positive group (n = 33) and hERO1‐α‐negative group (n = 38) in nuclear grade (P < 0.001) and intrinsic subtype (P = 0.021) in univariate analysis. More importantly, in multivariate analysis of disease‐free survival by Cox regression, expression of hERO1‐α was the only independent prognosis factor (P = 0.035). Finally, in univariate survival analysis, patients positive for hERO1‐α had significantly shorter disease‐free survival and overall survival than those patients negative for hERO1‐α. These findings indicate that the expression of hERO1‐α in cancer cells is associated with poorer prognosis and thus can be a prognostic factor for patients with breast cancer.
Survivin, a member of the inhibitor of apoptosis protein family, is widely expressed in a variety of human cancer tissues. Survivin inhibits activation of caspases, and its overexpression can lead to ...resistance to apoptotic stimuli. In this study, survivin protein expression was assessed by immunohistochemical staining of 195 invasive breast cancer specimens. Overall, 79.5% of the tumors were positive for survivin. The expression of epidermal growth factor receptor (EGFR) family, human epidermal growth factor receptor 2 (HER2) and EGFR, was also examined in 53 cases, and consequently, it was indicated that survivin positivity might be correlated with the coexpression of HER2 and EGFR. To clarify the regulatory mechanism of survivin expression in breast cancer cells, the effect of HER2 and/or EGFR expression on the survivin levels was examined. It was revealed that the survivin protein level was up-regulated by the coexpression of HER2 and EGFR, leading to the increased resistance against etoposide-induced apoptosis in breast cancer cells. Conversely, survivin levels and apoptosis resistance were decreased when cells were treated with HER2-specific inhibitor, Herceptin. Although Herceptin could down-regulate both phosphatidylinositol 3-kinase (PI3K)/AKT signal and mitogen-activated protein/extracellular signal-related kinase (ERK) kinase 1 (MEK1)/ERK signal in HER2-positive breast cancer cells, PI3K-specific inhibitor but not MEK1-specific inhibitor could decrease the survivin levels. The present study clarified the regulatory mechanism of HER2 in the expression of survivin protein in breast cancer cells.
Several genes that encode PR (PRDI-BF1 and RIZ) domain proteins (PRDM) have been linked to human cancers. To explore the role of the PR domain family genes in breast carcinogenesis, we examined the ...expression profiles of 16 members of the PRDM gene family in a panel of breast cancer cell lines and primary breast cancer specimens using semiquantitative real-time PCR. We found that PRDM14 mRNA is overexpressed in about two thirds of breast cancers; moreover, immunohistochemical analysis showed that expression of PRDM14 protein is also up-regulated. Analysis of the gene copy number revealed that PRDM14 is a target of gene amplification on chromosome 8q13, which is a region where gene amplification has frequently been detected in various human tumors. Introduction of PRDM14 into cancer cells enhanced cell growth and reduced their sensitivity to chemotherapeutic drugs. Conversely, knockdown of PRDM14 by siRNA induced apoptosis in breast cancer cells and increased their sensitivity to chemotherapeutic drugs, suggesting that up-regulated expression of PRDM14 may play an important role in the proliferation of breast cancer cells. That little or no expression of PRDM14 is seen in noncancerous tissues suggests that PRDM14 could be an ideal therapeutic target for the treatment of breast cancer.
The prevalence of transsexualism is thought to differ among socio-geographic backgrounds, and little is known about its prevalence in Japan. Polycystic ovary syndrome (PCOS), which is known to be ...associated with insulin resistance and metabolic syndrome, is often seen in female-to-male (FTM) transsexual patients. Consequently, detection of PCOS is an important part of health care for these individuals.
The purpose of this study was to assess the prevalence of transsexuality in Japan, as well as the incidences of PCOS and insulin resistance among Japanese FTM transsexual patients.
One hundred four male-to-female (MTF) and 238 FTM Japanese transsexual patients were studied. Medical histories, including histories of menstrual cycling and hormone treatment, were taken. To exclude other diseases, such as congenital adrenal hyperplasia and hormone-secreting tumors, thorough medical assessments, including transvaginal or transrectal ultrasonography and measurement of serum hormone levels and insulin resistance indexes, were performed.
The diagnosis of PCOS was based on the Rotterdam 2003 criteria.
Based on demographic statistics, the prevalences of MTF and FTM transsexuality are about 3.97 and 8.20 per 100,000 people, respectively, making the MTF-to-FTM ratio about 1:2. Of the FTM transsexual patients studied, 128 had not taken hormones before their initial assessment (untreated group); the remaining 50 self-administered androgen. Among the untreated group, 32.0% were diagnosed with PCOS, 30.1% were insulin-resistant, and 31.1% showed hypoadiponectinemia.
The sex ratio among Japanese transsexuals is different than among Caucasians. PCOS and insulin resistance are common findings in FTM transsexual patients at initial presentation. Baba T, Endo T, Ikeda K, Shimizu A, Honnma H, Ikeda H, Masumori N, Ohmura T, Kiya T, Fujimoto T, Koizumi M, and Saito T. Distinctive features of female-to-male transsexualism and prevalence of gender identity disorder in Japan.
We reported previously a HLA-A24-restricted antigenic peptide, survivin-2B80-88 (AYACNTSTL), recognized by CD8(+) CTL. This peptide was derived from survivin protein, an inhibitor of apoptosis ...proteins, expressed in a variety of tumors, such as adenocarcinoma, squamous cell carcinoma, and malignant melanoma. In this report, we provide further evidence that survivin-2B80-88 peptide might serve as a potent immunogenic cancer vaccine for various cancer patients. Overexpression of survivin was detected in surgically resected primary tumor specimens of most breast and colorectal cancers and some gastric cancers as assessed by immunohistochemical study. HLA-A24/survivin-2B80-88 tetramer analysis revealed that there existed an increased number of CTL precursors in peripheral blood mononuclear cells (PBMC) of HLA-A24(+) cancer patients, and in vitro stimulation of PBMCs from six breast cancer patients with survivin-2B80-88 peptide could lead to increases of the CTL precursor frequency. Furthermore, CTLs specific for this peptide were successfully induced from PBMCs in all 7 (100%) patients with breast cancers, 6 of 7 (83%) patients with colorectal cancers, and 4 of 7 (57%) patients with gastric cancers. These data indicate that survivin expressed in tumor tissues is antigenic in cancer patients, and survivin-2B80-88-specific CTLs are present in PBMCs of various cancer patients. Our study raises the possibility that this peptide may be applicable as a general cancer vaccine to a large proportion of HLA-A24(+) cancer patients.
Background
The objective of the present clinical study is to determine the maximum tolerated dose (MTD)/recommended dose (RD) of combination therapy with nanoparticle albumin-bound paclitaxel ...(nab-PTX) and cyclophosphamide (CPA) in patients with metastatic or recurrent breast cancer.
Methods
nab-PTX and CPA were administered on the first day of each 21-day treatment cycle. The dose of CPA was fixed at 600 mg/m
2
, while the dose of nab-PTX was increased from 180 mg/m
2
(Level 1) to 220 mg/m
2
(Level 2) and then to 260 mg/m
2
(Level 3).
Results
A total of 11 patients from two institutions were enrolled in the present study. At Level 3, a dose-limiting toxicity (DLT) was observed in 1 patient. Considering treatment continuity and the risk of adverse events in Cycle 2 and thereafter at this level, further subject enrollment at Level 3 was discontinued after two patients had been enrolled.
Since the doses used at Level 3 were considered the MTD of nab-PTX and CPA and the doses used at Level 2 were considered the RD of nab-PTX and CPA, three additional subjects were enrolled at Level 2. No DLTs were observed at Level 2.
Conclusion
The RD of combination therapy with nab-PTX and CPA was 220 mg/m
2
and 600 mg/m
2
, respectively, in patients with metastatic or recurrent breast cancer.
This randomized controlled trial will compare oral 5-fluorouracil derivatives, TS-1, with intravenous standard chemotherapy such as taxanes in women with metastatic or recurrent breast cancer. ...Patients with hormone-resistant breast cancer are assigned to either TS-1 (40–60 mg twice daily for 28 consecutive days, followed by a 14-day rest period) or standard chemotherapy (docetaxel 60–75 mg/m2 at 3- or 4-week intervals, paclitaxel 175 mg/m2 at 3- or 4-week intervals or paclitaxel 80–100 mg/m2 weekly, followed by a 1-week rest period). Treatment will be repeated until tumor progression or ≥4 courses for TS-1 and ≥6 courses for taxanes. The primary endpoint is overall survival. Secondary endpoints are progression-free survival, time to treatment failure, adverse events, health-related quality of life and cost-effectiveness. A threshold hazard ratio of 1.333 will be used to determine whether overall survival in the TS-1 group is equivalent (not inferior) to that in the taxane group. The target number of registered patients is 600.
Caspase-associated recruitment domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis. One of the CARD-containing proteins, TUCAN ...(CARD8), was reported previously as an antiapoptotic protein with a molecular weight of 48 kDa, which was up-regulated in colon cancer cells. We identified a novel isoform of TUCAN with a molecular weight of 54 kDa. The new variant of TUCAN, termed TUCAN-54, was expressed in gastric, colon, and breast cancer tissues but was barely detected in normal noncancerous tissues, whereas 48-kDa TUCAN was detected in tumor tissues and noncancerous tissues. To know the function of TUCAN-54 in the apoptosis of cancer cells, TUCAN-54 was overexpressed in tumor cells by gene transfection. Its overexpression inhibited pro-caspase-9 activation, leading to the suppression of the cell death induced by a protein kinase inhibitor, staurosporine, or a chemotherapeutic reagent, etoposide (VP-16). In contrast, specific small interfering RNA-mediated suppression of TUCAN-54 expression in tumor cells increased the VP-16-induced cell death rate, indicating that expression of TUCAN-54 might be associated with chemoresistance of tumor cells. In addition, it inhibited caspase-8 activation as well, thereby suppressing Fas-induced cell death. It was revealed that Fas-associated death domain was physically associated with TUCAN-54 but not with 48-kDa TUCAN. Thus, TUCAN-54 might be a novel tumor-specific antiapoptotic molecule expressed in a variety of human cancer tissues, which might aggravate malignant potential of cancer cells, such as chemoresistance and immunoresistance.
Background
Treatment outcome was evaluated in patients who underwent breast-conserving therapy and tangential irradiation. After verifying background factors including systemic therapy, the clinical ...efficacy of postoperative irradiation was investigated.
Method
There were 708 study subjects, all of whom had early breast cancer treated between 1992 and 2002. The median follow-up period was 83 months. After breast-conserving surgery, in patients with negative surgical margins, only tangential irradiation at 48 Gy/24 fr was performed. In contrast, in those with positive surgical margins, 10 Gy of radiation boost to the tumor bed with electrons was administered after tangential irradiation with 50 Gy/25 fr. Treatment outcome was analyzed using the Kaplan–Meier method and Cox’s proportional hazards regression model.
Results
The disease-free survival and no-recurrence rates within the ipsilateral breast after 5 years were 93.4 and 97.2%, respectively. Risk factors for recurrence within the ipsilateral breast included younger age of patient, the number of positive lymph nodes, and no endocrine therapy. However, the surgical margin was not a risk factor. Risk factors for relapse outwith the ipsilateral breast included younger age, the number of positive lymph nodes, and recurrence within the ipsilateral breast.
Conclusions
From our analysis of 708 Japanese women who received breast-conserving therapy, which can be regarded as a standard method in Japan, the treatment outcome was compatible with previous reports from other countries.
Breast cancer arises through the accumulation of multiple genetic alterations and epigenetic changes such as methylation, which silences gene expression in a variety of cancers. In the present study, ...we applied genomic screening to identify genes upregulated by the demethylating agent 5-aza-2′-deoxycytidine (DAC) in a human breast cancer cell line (MCF7). We identified 288 genes upregulated and 29 genes downregulated more than fivefold after treatment with DAC, and gene ontology analyses revealed the genes to be involved in immune responses, apoptosis, and cell differentiation. In addition, real-time PCR analysis of ten genes silenced in MCF7 cells confirmed that they are upregulated by DAC, while bisulfite-pyrosequencing analysis confirmed that nine of those genes were silenced by methylation. We also found that treating MCF7 cells with DAC restored induction of DFNA5 by p53, as well as by two other p53 family genes, p63γ and p73β. Introduction of NTN4 into MCF7 cells suppressed cell growth, indicating that NTN4 has tumor suppressive activity. In primary breast cancers, we detected cancer-specific methylation of NTN4, PGP9.5, and DKK3, suggesting that methylation of these genes could be useful markers for diagnosis of breast cancer. Thus, DNA methylation appears to be a common event in breast cancer, and the genes silenced by methylation could be useful targets for both diagnosis and therapy.
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