Biomedical subjects

Yasuo Miyoshi

Publications and source records attributed to Yasuo Miyoshi.

At least 19 recordsLinked to original sources

PubMed2007

Connexin26 expression is associated with lymphatic vessel invasion and poor prognosis in human breast cancer.

PURPOSE: Cx26, which is a constituent of the connexin family, has recently been shown to promote metastasis through enhancing the vascular invasion in mouse melanoma cells. In this study, we have investigated whether or not Cx26 expression is associated with vascular invasion and recurrences in human breast cancers. EXPERIMENTAL DESIGN: Cx26 expression was studied in 152 invasive breast cancers by immunohistochemistry. In order to investigate the blood vessel invasion and lymphatic vessel invasion with precision, immunohistochemical staining of blood vessels and lymphatic vessels was carried out using anti-CD34 and anti-D2-40 antibodies, respectively. RESULTS: Cx26 was positive in 51.3% (78/152) of the breast tumors. A statistically significant association was observed between Cx26 expression and large tumor size (P = 0.013) or high histological grade (P = 0.043). Frequency of blood vessel invasion was higher in Cx26-positive tumors (5.1%, 4/78) than in Cx26-negative tumors (1.4%, 1/74) though not statistically significant (P = 0.210). Lymphatic vessel invasion was significantly (P = 0.001) more frequent in Cx26-positive tumors (39.7%) than in Cx26-negative tumors (14.9%). Patients with Cx26-positive tumors showed a significantly (P < 0.001) poorer prognosis than those with Cx26-negative tumors. Multivariate analysis showed that Cx26 (P < 0.05) expression was an independent prognostic factor. CONCLUSIONS: Cx26 expression is associated with lymphatic vessel invasion, large tumor size, high histological grade, and poor prognosis in human breast cancers. Cx26 seems to enhance the metastasis probably through promoting the lymphatic vessel invasion. Cx26 might be clinically useful as a new prognostic factor.

Antibodies, Monoclonal↗

PubMed2007

Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women.

PURPOSE: Somatic mutations of PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase, have recently been shown to play an important role in the pathogenesis and progression of human breast cancers. In this study, the frequency of PIK3CA mutations and their relationship with clinicopathologic and biological variables were investigated in Japanese breast cancers. EXPERIMENTAL DESIGN: Mutational analysis of PIK3CA was done in 188 primary breast cancers of Japanese women. Relationship of these mutations with various clinicopathologic variables [histologic type, tumor size, histologic grade, lymph node status, estrogen receptor (ER)-alpha and progesterone receptor status, and prognosis], biological variables [phospho-AKT (pAKT) and HER2 expression determined by immunohistochemistry], and p53 mutation status was studied. RESULTS: Missense mutations of PIK3CA were found in 44 of 158 invasive ductal carcinomas, 4 of 10 invasive lobular carcinomas, 1 of 4 mucinous carcinomas, 2 of 2 squamous carcinomas, and 2 of 2 apocrine carcinomas, but no mutation was found in 12 noninvasive ductal carcinomas. PIK3CA-mutated tumors were found to be more likely to be ER-alpha positive (P < 0.05) and pAKT positive (P < 0.05). There was no significant association between PIK3CA mutations and p53 mutation status. PIK3CA mutations were significantly (P < 0.05) associated with a favorable prognosis, and multivariate analysis showed that PIK3CA mutation status was a significant (P < 0.05) prognostic factor independent of the other conventional prognostic factors. CONCLUSIONS: The frequency of PIK3CA mutations in Japanese breast cancers is similar to that of Caucasian breast cancers. Association of PIK3CA mutations with positive pAKT and positive ER-alpha suggests that PIK3CA mutations might exert their effects through activation of the phosphatidylinositol 3-kinase/AKT/ER-alpha pathway. PIK3CA mutations seem to have a potential to be used as an indicator of favorable prognosis.

Breast Neoplasms↗

PubMed2006

Demonstration of adiponectin receptors 1 and 2 mRNA expression in human breast cancer cells.

Recently, we have shown that low adiponectin levels are significantly associated with an increased breast cancer risk. It seems to be very important to study the expression of adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2) in the human breast epithelial cells and breast cancer cells in order to clarify whether or not adiponectin exerts its effects directly on these cells. Expression of adiponectin, AdipoR1, and AdipoR2 mRNA was determined by RT-PCR assay using the RNA samples obtained from human breast cancer cell lines (MCF-7, T47D, SKBR3, and MDA-MB231), HMEC (primary culture of normal human mammary epithelial cells), adipose tissues (axilla) as well as breast cancer cells and normal breast epithelial cells selectively collected from breast cancer tissues by laser microdissection (LMD). Adiponectin mRNA expression was observed only in the adipose tissues. On the other hand, AdipoR1 and AdipoR2 mRNA expression was observed in all four breast cancer cell lines, HMEC, adipose tissues as well as breast cancer cells and normal breast epithelial cells selectively collected by LMD. In addition, AdipoR1 and AdipoR2 expression in both normal breast epithelial cells and breast cancer cells was confirmed by immunohistochemistry. These results suggest a possibility that adiponectin might modulate the growth of normal breast epithelial cells and breast cancer cells directly through AdipoR1 and AdipoR2 receptors, and that the association of low serum adiponectin levels with a high breast cancer risk might be explained, at least in part, by the direct effect of adiponectin on the breast epithelial cells.

Adiponectin↗

PubMed2006

Association of GSTP1 CpG islands hypermethylation with poor prognosis in human breast cancers.

Glutathione S-transferase P1 (GSTP1) belongs to a family of phase II metabolic enzymes that can detoxify the carcinogens and cytotoxic drugs by conjugating them with glutathione. Relationship of GSTP1 CpG islands hypermethylation or GSTP1 protein expression with clinicopathological characteristics of breast cancers was studied. The CpG islands hypermethylation status of GSTP1 gene was studied by methylation specific primer assay and GSTP1 expression was studied by immunohistochemistry in primary breast cancers. Of 174 breast tumors, 24 (14%) were found to have GSTP1 CpG islands hypermethylation. A significant association was found between GSTP1 CpG islands hypermethylation and large tumor size (P < 0.01) or lymph node metastases (P < 0.05). Relapse-free survival (RFS) rates of patients with GSTP1 CpG islands hypermethylation were significantly poorer than those without it (5-year RFS rates; 60 vs. 86%, P < 0.01). Multivariate analysis showed that GSTP1 CpG islands hypermethylation status was a statistically significant prognostic factor being independent of other conventional prognostic factors. Immunohistochemical study showed that here was a significant association between GSTP1 CpG islands hypermethylation and loss of GSTP1 expression (P < 0.01) but that RFS rates of patients with GSTP1 positive tumors were not significantly different from those with GSTP1 negative tumors. GSTP1 CpG islands hypermethylation, but not GSTP1 protein expression, is associated with a poor prognosis of breast cancers, suggesting that GSTP1 CpG islands hypermethylation has a potential to serve as a clinically useful prognostic factor.

Breast Neoplasms↗

PubMed2006

Quantitative analysis of aromatase mRNA expression derived from various promoters (I.4, I.3, PII and I.7) and its association with expression of TNF-alpha, IL-6 and COX-2 mRNAs in human breast cancer.

The purpose of the present study was to study the aromatase mRNA expression as well as promoter usage (I.4, I.3, PII and I.7) in axillary adipose tissue (AA), mammary adipose tissue (MA), breast tumor tissue (BT) and adjacent normal breast tissue (NB), and to study the relationship between aromatase mRNA expression and tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and cyclooxygenase (COX)-2 mRNA expression. BT (n=108), NB (n=54), AA (n=41) and MA (n=34) from patients with breast cancer were subjected to real-time PCR assays for the mRNA levels of aromatase, TNF-alpha, IL-6 and COX-2. We also studied the usage of promoters I.4, I.3, PII and the recently reported endothelial promoter I.7. Total aromatase mRNA levels were significantly up-regulated in BT as compared with NB, AA and MA. Proportion of promoter l.4-specific transcripts against the total transcripts was significantly decreased and that of promoter l.3- and l.7-specific transcripts was significantly increased in BT than NB, AA and MA. However, the amount of transcripts from all the 4 promoters was significantly up-regulated in BT than NB, AA and MA. Estrogen receptor-alpha (ER-alpha) positive tumors showed a higher percentage of promoter I.7 usage than ER-alpha negative tumors with a marginal significance (p=0.05), and tumor with high microvessel counts tended (p=0.06) to show a higher percentage of promoter I.7 usage than those with low microvessel counts. There was a significant association between aromatase mRNA levels and TNF-alpha, IL-6 or COX-2 mRNA levels in BT, AA and MA but not in NB. These results suggest that enhanced transcription of promoters l.4, I.3, PII and I.7 explains the up-regulation of aromatase mRNA levels in BT. It has also been suggested that angiogenesis might stimulate the growth of ER-alpha positive tumors through the enhanced transcription of aromatase from promoter I.7 in endothelial cells in BT, and that TNF-alpha, IL-6 and COX-2 might be implicated in the up-regulation of aromatase mRNA in BT, AA and MA but not in NB.

Adipose Tissue↗

PubMed2006

Quantitative analysis of aromatase, sulfatase and 17beta-HSD(1) mRNA expression in soft tissue metastases of breast cancer.

Expression of the estrogen-synthesizing genes aromatase, steroid sulfatase (STS) and 17beta-hydroxysteroid dehydrogenase type1 (17beta-HSD(1)) has been shown to be up-regulated in primary breast cancer tissue but their expression status in metastatic tumor tissue has yet to be determined. The mRNA expression levels of the three estrogen-synthesizing genes as well as of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and cyclooxygenase (COX)-2, all of which have been reported to up-regulate the estrogen-synthesizing genes, were determined by means of a real-time PCR assay in 100 primary breast cancer tissues and 15 soft tissue metastases. In addition, PCR-gel electrophoresis was used to determine the proportion (%) of promoter (l.4, l.3, Pll and l.7) usage of aromatase. Aromatase and STS mRNA levels were significantly (P=0.04 and P=0.03, respectively) higher in soft tissue metastases than in primary tumors, while 17beta-HSD(1) mRNA levels tended (P=0.09) to be higher. The proportions of the promoter usages were very similar for primary tumors and soft tissue metastases, and the mRNA levels of TNF-alpha, IL-6 and COX-2 were not significantly different. Levels of aromatase, STS and 17beta-HSD(1) mRNA are up-regulated in soft tissue metastases compared to those in primary tumors, suggesting that intra-tumoral estrogen synthesis may play a significant role in the growth stimulation of tumor cells in soft tissue metastases as in primary tumors. TNF-alpha, IL-6 and COX-2, on the other hand, are unlikely to be implicated in this up-regulation.

17-Hydroxysteroid Dehydrogenases↗

PubMed2006

High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels.

The association of mRNA expression levels of leptin receptors (long isoform: Lep-R(L) and short isoform: Lep-R(S)) in breast cancer tissue with patient prognosis was studied with special reference to the serum leptin level or the leptin mRNA level in tumor tissue. Lep-R(L), Lep-R(S) and leptin mRNA levels in breast cancer tissue (n = 91) were determined with a real-time PCR assay, and serum leptin levels in breast cancer patients (n = 67) with an enzyme-linked immunosorbent assay. Neither Lep-R(L) nor Lep-R(S) mRNA levels in tumor tissue were significantly associated with patient prognosis, but both intratumoral Lep-R(L) and Lep-R(S) mRNA high tumors were significantly (p < 0.01) associated with a poor prognosis. Multivariate analysis showed that a high level of both Lep-R (L) and Lep-R (S) mRNA in tumor tissue was a significant risk factor, independent of other risk factors. The subset analysis demonstrated that both intratumoral Lep-R(L) and Lep-R(S) mRNA high tumors were significantly associated with a poor prognosis for the subset of patients with high serum leptin or high intratumoral leptin mRNA levels but not in the subset of patients with low serum leptin or low intratumoral leptin mRNA levels. The association between both intratumoral Lep-R(L) and Lep-R(S) mRNA high tumors and a poor prognosis in the presence of high serum leptin or high intratumoral leptin mRNA levels seems to suggest that the leptin and Lep-R(L)/Lep-R(S) pathways are implicated in the growth stimulation of breast tumors. The well-established finding that obesity serves as a risk factor for relapse in breast cancer patients may thus be partially explained by the high serum leptin level seen in obese women.

Adult↗

PubMed2006

High expression of ubiquitin carboxy-terminal hydrolase-L1 and -L3 mRNA predicts early recurrence in patients with invasive breast cancer.

The present study investigated the mRNA expression level of ubiquitin c-terminal hydrolase (UCH)-L1 and -L3 in breast cancer tissue and aimed to elucidate its association with tumor characteristics and patient prognosis. UCH-L1 and UCH-L3 mRNA levels in invasive breast cancer (n = 100) were determined by a real-time polymerase chain reaction (PCR) assay and their relationship with various clinicopathological characteristics of breast tumors as well as patient prognosis were studied. UCH-L3 mRNA level was significantly upregulated in breast cancer tissue compared to adjacent normal breast tissue (P < 0.005), and UHC-L1 mRNA level also showed a non-significant increase in tumor tissue compared to adjacent normal breast tissue. Both UCH-L1 and UCH-L3 mRNA levels were significantly higher in high histological grade tumors than in low histological grade tumors (P < 0.001 and P < 0.005, respectively). High UCH-L1 mRNA level was significantly associated with negative estrogen receptor status (P < 0.05) and negative progesterone receptor status (P < 0.05). Patients with both UCH-L1 and UCH-L3 mRNA high tumors showed a significantly poorer prognosis than those in the UCH-L1 or UCH-L3 mRNA low group (P < 0.005). These observations that UCH-L3 mRNA level is upregulated in breast cancer tissue, and breast tumors with both UCH-L1 and UCH-L3 mRNA high expression are associated with a poor prognosis, suggest the possible involvement of UCH-L1 and UCH-L3 in the pathogenesis and progression of breast cancer.

Antigens, CD↗

PubMed2006

Clinical significance of class III beta-tubulin expression and its predictive value for resistance to docetaxel-based chemotherapy in gastric cancer.

Docetaxel, one of the most effective anticancer drugs for gastric cancer, targets beta-tubulin, the major protein in mitotic spindles. Eight isotypes of beta-tubulin, with tissue and organ-specific expression, have been identified in mammalian cells. We examined class III beta-tubulin expression in gastric cancer and assessed its relationship with sensitivity to docetaxel-based chemotherapy. A total of 115 paraffin-embedded gastric tumors were analyzed by immunohistochemistry for class III beta-tubulin expression. Twenty patients with advanced gastric cancer received preoperative docetaxel-based chemotherapy. Their biopsied specimens, obtained by endoscopy before chemotherapy were examined for class III beta-tubulin expression. The relationship between expression and chemosensitivity was assessed. Forty-two (36.4%) of 115 cases were confirmed to be positive for class III beta-tubulin expression. There was no association between clinicopathological status and prognosis. Among the patients positive for class III beta-tubulin expression, only 16.7% showed no response to chemotherapy, while 64.3% responded to the chemotherapy in the negative group. Our results suggest that class III beta-tubulin is a simple and useful predictive marker for the clinical response to docetaxel-based chemotherapy in gastric cancer.

Adult↗

PubMed2005

High thioredoxin expression is associated with resistance to docetaxel in primary breast cancer.

PURPOSE: Thioredoxin overexpression is suggested to be associated with resistance to several chemotherapeutic agents in vitro. In the present study, it has been studied whether or not high thioredoxin expression is associated with resistance to docetaxel therapy in breast cancer patients. PATIENTS AND METHODS: Sixty-three primary breast cancer patients were treated with docetaxel (60 mg/m(2), q3w) for four cycles in the neoadjuvant setting. Expression of thioredoxin, estrogen receptor (ER), p53, BRCA-1, and Bcl-2 in tumor tissues obtained before docetaxel therapy was studied by immunohistochemistry (thioredoxin, p53, BRCA-1, and Bcl-2) and enzyme immunoassay (ER), and relationship of expression of these biomarkers with a pathologic response was investigated. RESULTS: There was no significant correlation between the expression of p53, BRCA-1, or Bcl-2 and a response to docetaxel. However, tumors with high thioredoxin expression showed a significantly lower response rate (0%) than those with low thioredoxin expression (30.6%; P = 0.018) and ER-negative tumors showed a significantly higher response rate (32.4%) than ER-positive tumors (10.7%; P = 0.043). Thioredoxin expression significantly increased after docetaxel therapy (mean, 56.1%) as compared with that before docetaxel therapy (mean, 28.6%; P < 0.0001) but there was no significant association between the extent of increase in thioredoxin expression and response. CONCLUSION: High thioredoxin expression in prechemotherapy tumor samples, but not the increase in thioredoxin expression induced by docetaxel, is associated with resistance to docetaxel in breast cancer. Thioredoxin and ER might be clinically useful in the prediction of a response to docetaxel.

Antineoplastic Agents, Phytogenic↗

PubMed2005

Differentiation of follicular thyroid adenoma from carcinoma by means of gene expression profiling with adapter-tagged competitive polymerase chain reaction.

OBJECTIVE: Since preoperative differentiation between follicular thyroid adenoma (FTA) and carcinoma (FTC) remains very difficult, the purpose of this study was to identify the genes differentially expressed in FTA and FTC in order to construct a diagnostic system based on such genes for differentiation of FTA and FTC. METHODS: Gene expression profiles of 45 FTAs and 22 FTCs were analyzed by means of adapter-tagged competitive polymerase chain reaction (ATAC-PCR) with 2,516 genes (learning set). The genes differentially expressed in FTAs and FTCs were then used to construct a diagnostic system based on the weighted-voting algorithm. In addition, a validation study of this diagnostic system was conducted using 12 FTAs and 6 FTCs (validation set). RESULTS: The diagnostic system for differentiation of FTA and FTC, constructed with the aid of the learning set samples, was based on 60 genes differentially expressed in FTA and FTC, which included several genes previously identified as overexpressed in FTC (DPP4, KRT19 and IGFBP3) or FTA (trefoil factor 3 and thyroid peroxidase). The leave-one-out cross-validation study showed that the accuracy of this diagnostic system was as high as 90% (sensitivity: 77.3% and specificity: 95.6%), and was confirmed by the validation study (diagnostic accuracy: 83.3%; 95% confidence interval: 62.8-95.4%, sensitivity: 66.7% and specificity: 91.2%). CONCLUSIONS: This diagnostic system using the ATAC-PCR assay is expected to be clinically useful for preoperative differentiation between FTA and FTC since ATAC-PCR can be used for the small amount of RNA obtained from fine needle aspiration biopsy.

Adenoma↗

PubMed2005

Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers.

PURPOSE: LATS1 and LATS2 are tumor suppressor genes implicated in the regulation of cell cycle. Methylation status of the promoter regions of these genes as well as its correlation with their mRNA levels were studied in human breast cancers. Correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics of breast tumors were also studied. EXPERIMENTAL DESIGN: Methylation status of promoter regions of LATS1 and LATS2 was studied by a methylation-specific PCR and mRNA expression levels of LATS1 and LATS2 were determined by a real-time PCR assay in 30 breast cancers. In addition, correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics was studied in 117 breast cancers. RESULTS: Methylation-specific PCR showed that of 30 tumors, LATS1 promoter region was hypermethylated in 17 tumors (56.7%) and LATS2 promoter region was hypermethylated in 15 (50.0%) tumors. LATS1 mRNA levels in breast tumors with hypermethylation (2.15 +/- 0.37, mean +/- SE) were significantly (P < 0.01) lower than those without hypermethylation (6.09 +/- 1.38), and LATS2 mRNA levels in breast tumors with hypermethylation (1.42 +/- 0.66) were also significantly (P < 0.01) lower than those without hypermethylation (3.10 +/- 1.00). The decreased expression of LATS1 or LATS2 mRNA was significantly associated with a large tumor size, high lymph node metastasis, and estrogen receptor and progesterone receptor negativity. Furthermore, the decreased expression of LATS1 mRNA, but not LATS2 mRNA, was significantly (P < 0.05) associated with a poor prognosis. CONCLUSIONS: Hypermethylation of the promoter regions of LATS1 and LATS2 likely plays an important role in the down-regulation of their mRNA levels in breast cancers, and breast cancers with a decreased expression of LATS1 or LATS2 mRNA levels have a biologically aggressive phenotype.

Adult↗

PubMed2005

Prediction of docetaxel response in human breast cancer by gene expression profiling.

PURPOSE: Docetaxel is one of the most effective anticancer drugs available in the treatment of breast cancer. Nearly half of the treated patients, however, do not respond to chemotherapy and suffer from side effects. The ability to reliably predict a patient's response based on tumor gene expression will improve therapeutic decision making and save patients from unnecessary side effects. PATIENTS AND METHODS: A total of 44 breast tumor tissues were sampled by biopsy before treatment with docetaxel, and the response to therapy was clinically evaluated by the degree of reduction in tumor size. Gene expression profiling of the biopsy samples was performed with 2,453 genes using a high-throughput reverse transcriptase polymerase chain reaction technique. Using genes differentially expressed between responders and nonresponders, a diagnostic system based on the weighted-voting algorithm was constructed. RESULTS: This system predicted the clinical response of 26 previously unanalyzed samples with over 80% accuracy, a level promising for clinical applications. Diagnostic profiles in nonresponders were characterized by elevated expression of genes controlling the cellular redox environment (ie, redox genes, such as thioredoxin, glutathione-S-transferase, and peroxiredoxin). Overexpression of these genes protected cultured mammary tumor cells from docetaxel-induced cell death, suggesting that enhancement of the redox system plays a major role in docetaxel resistance. CONCLUSION: These results suggest that the clinical response to docetaxel can be predicted by gene expression patterns in biopsy samples. The results also suggest that one of the molecular mechanisms of the resistance is activation of a group of redox genes.

Adult↗

PubMed2005

Usefulness of three-dimensional multidetector-row CT images for preoperative evaluation of tumor extension in primary breast cancer patients.

PURPOSE: Usefulness of three dimensional (3D) multidetector-row CT (MDCT) images for preoperative evaluation of tumor extension was studied in primary breast cancer patients. METHODS: 3D-MDCT tumor images of 143 tumors in 143 patients with primary breast cancer were created with the volume rendering method. The transverse tumor size (TS) and vertical tumor size (VS) were then measured in an anterior-posterior view of the 3D-MDCT images. The pathological tumor size was determined according to a map of the tumor spread prepared by pathologists using multi-sliced (3-5 mm intervals) surgical specimens and compared with the tumor size on 3D-MDCT images. RESULTS: First, the optimal method for creating 3D-MDCT tumor images was determined for the first 40 patients (learning set), resulting in a fairly good correlation of tumor size on 3D-MDCT images with pathological tumor size (r = 0.983 for TS and r = 0.958 for VS). We then carried out a validation study on the next 103 patients (validation set). The 3D-MDCT tumor size's strong correlation with the pathological tumor size demonstrated a high rate of accuracy (r = 0.974 for TS and r = 0.977 for VS). Subset analyses according to histological type showed that correlation coefficients were r = 0.979 for TS and r = 0.981 for VS of invasive ductal carcinomas (n = 88), r = 0.948 for TS and r = 0.970 for VS of ductal carcinomas in situ (n = 10), and r = 0.984 for TS and r = 0.976 for VS of invasive lobular carcinomas (n = 5). CONCLUSION: 3D-MDCT images can assess breast cancer tumor extension highly accurately, and thus seems to be useful for planning the extent of resection in breast conserving surgery.

Adult↗

PubMed2005

Possible involvement of aromatase overexpression induced by cyclo-oxygenase-2 in the pathogenesis of idiopathic gynecomastia.

The pathogenesis of idiopathic gynecomastia, which shows no imbalance in serum estrogens and androgens levels unlike gynecomastia of other causes, is unknown. It seems to be of interest to study the in situ aromatase expression in idiopathic gynecomastia to investigate a possible involvement of intratumoral biosynthesis of estrogens in the pathogenesis of this disease. The expression level of aromatase mRNA was studied by a real-time polymerase chain reaction (PCR) assay in four idiopathic gynecomastia cases (two florid type and two fibrous type). In addition, the proportion of promoter usage (promoters I.3 I.4, l. 7, and PII) of the aromatase gene was determined by PCR-gel electrophoresis. Localization of aromatase and cyclo-oxygenase-2 (COX-2) expression was studied by immunohistochemistry. The aromatase mRNA level of the florid type gynecomastia (3.05 and 1.66) was higher than that in the fibrous type (0.76 and 0.04). The proportion of promoter Pll in the florid type (94.1% and 84.8%) was very high as compared with that of the fibrous type (0.7% and 0.5%). Immunohistochemical studies have revealed that aromatase and COX-2 were strongly expressed in the duct epithelial cells in the florid type, but they were weak or negative in the fibrous type. COX-2 is suggested to upregulate aromatase expression by enhancing the transcription via promoter Pll in idiopathic gynecomastia of the florid type but not of the fibrous type. Because idiopathic gynecomastia initially develops as the florid type and regresses as the fibrous type, a high estrogen milieu induced by increased aromatase expression is speculated to play some role in the pathogenesis of idiopathic gynecomastia.

Adolescent↗

PubMed2005

Prediction of response to docetaxel by immunohistochemical analysis of CYP3A4 expression in human breast cancers.

BACKGROUND: Docetaxel (DOC) is inactivated by CYP3A4, high expression of which in tumor tissue might serve as a resistance mechanism. In the present study, the CYP3A4 protein level in breast cancers was determined by immunohistochemistry, and its relationship with the response to DOC treatment was studied. MATERIALS AND METHODS: Thirty-one patients with locally advanced (n = 21) or recurrent (n = 10) breast cancers underwent tumor biopsy, followed by DOC treatment (60 mg/m2 q3w). Expression of CYP3A4 was studied by immunohistochemistry. RESULTS: Patients with CYP3A4 negative tumors (n = 15) by immunohistochemistry showed a significantly (P < 0.01) higher response rate (67%) to DOC treatment than those with CYP3A4 positive tumors (n = 16, 19%). The positive predictive value, negative predictive value, and diagnostic accuracy of CYP3A4 expression by immunohistochemistry in the prediction of response to DOC were 67%, 81%, and 74%, respectively. CONCLUSION: Immunohistochemical analysis of CYP3A4 expression in tumor cells might be clinically useful in the prediction of tumor response to DOC.

Adult↗

PubMed2005

[The feasibility of FEC (75) as adjuvant chemotherapy for Japanese breast cancer patients].

Recently, high-dose FEC (fluorouracil, epirubicin, and cyclophosphamide) has been increasingly used in adjuvant chemotherapy for breast cancer in Japan. However, the safety and tolerability of high-dose FEC are not well evaluated in Japanese breast cancer patients. We studied the feasibility of FEC (75) (fluorouracil: 500 mg/m(2), epirubicin: 75 mg/m(2), and cyclophosphamide:500 mg/m(2), q 3 w, 6 cycles) as adjuvant chemotherapy for 59 primary breast cancer patients. Out of these patients, 56 (94.9%) finished 6 cycles-FEC. The mean epirubicin dose received was 431.7 mg/m(2) (95.9% of the intended dose of 450 mg/m(2)). Forty-five (76.2%) of 59 patients experienced neutropenia of grade 3 or 4, while the rates of febrile neutropenia (grade 3) and infection (grade 2) were 3.4% and 10.2%, respectively. Anemia (88.2%), fatigue (42.4%), nausea (40.6%), liver dysfunction (40.7%), and vomiting (18.7%) occurred, however most of them were mild and categorized into grade 1 or 2. No patients developed any cardiac failure symptoms. This study shows FEC (75) is well tolerable as adjuvant chemotherapy for Japanese breast cancer patients.

Adult↗

PubMed2004

Down-regulation of intratumoral aromatase messenger RNA levels by docetaxel in human breast cancers.

PURPOSE: The reason why chemotherapy induces resistance to subsequent hormonal therapy remains to be clarified in postmenopausal breast cancers. We hypothesized that chemotherapy might down-regulate the intratumoral biosynthesis of estrogens. Thus, we have studied the influence of chemotherapy (docetaxel) on intratumoral aromatase mRNA expression because aromatase is a key enzyme for intratumoral biosynthesis of estrogens. EXPERIMENTAL DESIGN: The mRNA levels of aromatase and its inducers [tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and cyclooxygenase 2 (COX-2)] were determined by a real-time polymerase chain reaction assay in breast cancer tissues obtained before and after neoadjuvant chemotherapy with docetaxel (four cycles of 60 mg/m2 every 3 weeks) in 16 postmenopausal patients with estrogen receptor (ER)- and/or progesterone receptor (PR)-positive breast cancers. ER and PR levels in tumor tissues were also determined by enzyme immunoassay before and after chemotherapy. RESULTS: The intratumoral aromatase mRNA levels decreased significantly (P < 0.05) after chemotherapy from 0.84 +/- 0.28 (mean +/- SE) to 0.47 +/- 0.28. The intratumoral TNF-alpha mRNA levels also decreased significantly (P < 0.05) after chemotherapy from 2.40 +/- 0.52 to 0.95 +/- 0.25. On the contrary, the intratumoral IL-6 and COX-2 mRNA levels showed a marginally significant increase (P = 0.07) and a significant increase (P < 0.05), respectively, after chemotherapy. PR levels showed a marginally significant decrease (P = 0.08) after chemotherapy, whereas ER levels were almost constant before and after chemotherapy. CONCLUSIONS: Antitumor activity of docetaxel is mediated, at least in part, through a down-regulation of aromatase expression in tumor tissues, resulting in the suppression of intratumoral estradiol synthesis. Aromatase expression seems to be regulated mostly by TNF-alpha, but not IL-6 and COX-2.

Aged↗