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Loss of Heterozygosity of Major Tumor Suppressor Genes in Invasive Ductal Carcinomas.

Woo Seok BYUN ; Chan Heun PARK ; Seong Jin CHO ; Hye Gyung AHN ; Eun Sook NAM ; Hee Jung CHA ; Kwan Suk KIM

Journal of Breast Cancer.2007;10(1):68-76. doi:10.4048/jbc.2007.10.1.68

PURPOSE: Breast cancer is one of the most frequent malignant tumors in Korea. The major tumor suppressor genes (TSGs) such as p16, Rb, E-cadherin and p53 may play important roles in cell cycle regulation, apoptosis and the regulation of the expression of other genes as well as tumor suppression. Microsatellite alteration such as loss of heterozygosity (LOH) have been reported to be a novel mechanism of carcinogenesis and a useful prognostic factor for many malignant tumors. Also, LOH is also known to be related with allelic loss of various TSGs. This study evaluated LOH of 4 TSGs in invasive ductal carcinomas (IDCs) and we correlated these results with the clinicopathological factors. METHODS: LOH analysis was carried out using a polymerase chain reaction with 12 polymorphic microsatellite markers of 4 TSGs in 50 surgically resected tumors and their non-tumorous counterparts. RESULTS: There was no detectable LOH in the normal tissue. LOH was detected in 86% of the 50 cases of IDCs. LOH was detected on all chromosomes and this showed a statistical difference between benign tumor and malignant tumor. LOH of p16, Rb, E-cadherin and p53 TSGs was detected in 36%, 26%, 54% and 60% of the tumors, respectively. LOH of the p16 and Rb genes was inversely correlated with tumor grade 1. The low rate of detecting LOH on the E-cadherin gene was noted in T1 tumor and stage I disease. LOH of the p53 gene correlated well with the tumor size and stage. The LOH-High results correlate well with the tumor size and stage and the LOH-High results are similar to those of the p53 gene LOH. CONCLUSION: These results suggest that LOH of the 4 major TSGs may contribute to the development and invasion of IDCs. Also, the combined use of various LOH markers may help in deciding the prognosis of IDCs.
Apoptosis ; Breast Neoplasms ; Cadherins ; Carcinogenesis ; Carcinoma, Ductal* ; Cell Cycle ; Genes, p53 ; Genes, Retinoblastoma ; Genes, Tumor Suppressor* ; Korea ; Loss of Heterozygosity* ; Microsatellite Repeats ; Polymerase Chain Reaction ; Prognosis

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Association between Promoter Hypermethylation of the p16INK4a and hTERT Genes and Their Protein Expressions in Human Breast Cancer.

Su Min LEE ; Hyeon Woo YIM ; Ahwon LEE ; Woo Chan PARK ; Je Seung LEE ; Won Chul LEE

Journal of Breast Cancer.2007;10(1):59-67. doi:10.4048/jbc.2007.10.1.59

PURPOSE: This study was undertaken to observe the pattern of methylation of the p16INK4a and human telomerase reverse transcriptase (hTERT) genes and the p16 and hTERT protein expressions in invasive ductal carcinoma of the breast. In addition, we evaluated the relationship between the methylation status of the two genes and their protein expressions. METHODS: We performed methylation-specific PCR (MSP) and immunohistochemical staining in 63 breast cancer specimens. RESULTS: There was no statistical association between p16INK4a gene methylation and the histological grade (tumor grade, tumor size and lymph node status). Methylation of the hTERT promoter did show significant differences according to the histological tumor grade and tumor size, but there was no clinical significance. Methylation of the p16INK4a and hTERT genes was found in 22.2% and 31.8% of the specimens, respectively. A negative p16 protein expression (0-10% expression rate) was observed in 38.1% of the specimens (24 of 63). A positive hTERT expression (more than a 25% expression rate) was observed in 73.0% of the specimens (46 of 63). There was no statistical significance in the relationship between the methylation status and the protein expression. CONCLUSION: Our data suggest that methylation of the p16 and hTERT genes is not associated with their protein expressions according to Immunohistochemisty. There seemed to be another complicated mechanism for p16 inactivation and hTERT activation in breast cancer.
Breast Neoplasms* ; Breast* ; Carcinoma, Ductal ; Genes, p16 ; Humans* ; Lymph Nodes ; Methylation ; Polymerase Chain Reaction ; Telomerase

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Methylation Patterns of Cancer-Associated Genes in Breast Cancer.

Sung Bae JEE ; Woo Chan PARK ; Kee Whan KIM ; Ji Il KIM ; Chang Hyeok AHN ; Keun Woo LIM ; Se Jung OH ; Byung Joo SONG ; Sang Seol JUNG ; Jeong Soo KIM

Journal of Breast Cancer.2007;10(1):51-58. doi:10.4048/jbc.2007.10.1.51

PURPOSE: To investigate the methylation status of cancerassociated genes in breast cancer to assess its use in the diagnosis of breast cancer and the relationship with distinctive clinical and pathological features. METHODS: A total of 29 benign tumors and their adjacent normal tissues as well as 67 malignant tumors and adjacent normal samples, from women undergoing surgery for primary invasive breast carcinoma at Uijongbu St. Mary's Hospital, between March 2003 and March 2005, were used. Eleven candidate genes were chosen; P14, P16, DAPK, MGMT, h-MLH, E-cadherin, RASSF1 , Twist, RAR , HIN-1, and Cyclin D. DNA was extracted from fresh tissues, and methylation specific PCR performed. RESULT: The number of methylated genes was increased in the malignant tissues compared to the benign tumors and adjacent normal tissues. 7 genes; P14, P16, MGMT, RASSF1, Twist, RAR beta and Cyclin D, were more frequently methylated in malignant than benign tumors, with the differences in the p14, p16, and RAR beta genes were statistically significant (p<0.05). In benign tumors, the p16 and HIN-1 genes were the most infrequently (6.9%) and frequently methylated (82.8 %), respectively. In malignant tumors, the h-MLH and RASSF1 genes were most infrequently and frequently methylated genes, respectively. The ubgroup showing methylation of the DAPK gene had a higher nuclear grade and greater progesterone receptor negativity. The group in which the RASSF1 gene was methylated, had greater estrogen receptor (ER) and progesterone receptor (PgR) positivities. The Twist gene was frequently methylated in the subgroup showing higher nuclear and histologic grades. The group with HIN- 1 and cyclin D methylation had a tendency to show greater ER positivity. CONCLUSION: The subgroups showing methylated DAPK and Twist should be more intensely treated and followed up more carefully than those with RASSF1 , HIN-1 and Cyclin D methylation. Gene methylation may be linked to various pathological features of breast cancer; however, this will require confirmation from larger studies.
Breast Neoplasms* ; Breast* ; Cadherins ; Cyclin D ; Diagnosis ; DNA ; Estrogens ; Female ; Genes, Tumor Suppressor ; Humans ; Methylation* ; Polymerase Chain Reaction ; Receptors, Progesterone

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Role of Zoledronic Acid on Bone Loss by Letrozole.

Byung Joo SONG ; Seon Wook CHA ; Ja Seong BAE ; Young Jin SEO ; Woo Chan PARK ; Han Seong KIM ; Se Jung OH ; Jeong Soo KIM ; Sang Seol JUNG

Journal of Breast Cancer.2007;10(1):43-50. doi:10.4048/jbc.2007.10.1.43

PURPOSE: The aromatase inhibitors cause bone loss by estrogen depletion. Zoledronic acid (ZA) can prevent bone mineral density (BMD) loss associated with the use of aromatase inhibitors. Accordingly interest has arisen in measuring surrogate markers of bone resorption to monitor the response of treatment of BMD loss in place of a radiologic assessment. This study was designed to determine whether ZA would prevent bone loss that is known to occur with letrozole and identified surrogate markers of bone resorption in an animal model. METHODS: In ovariectomized or sham-operated rat, we administrated ZA and letrozole to 5 different groups including: a sham operation control group (OC), a group in which an ovariectomy was performed followed by saline administration (OS), an ovariectomy with ZA treatment group (OZ), an ovariectomy with letrozole treatment group (OL) and an ovariectomy with ZA and letrozole combined treatment group (OZL). The levels of serum osteocalcin, serum bone alkaline phosphatase (BALP), serum calcium and urine N-telopeptide (NTX) and BMD were estimated and compared at the same periods for each group. The distinct microscopic findings of proximal tibia at week sixteen were also compared. RESULTS: Significantly reduced levels of urine NTX and significantly increased BMD were measured in the OZ group. In the OL group no difference was seen in in BMD in comparison to the OS group. However, a significant increase in BMD was measured in the OZL group. Urine NTX levels were measured and found to be lower in the OL group and significantly lower in the OZL group. Serum osteocalcin levels were similar to each other for each group. Levels of serum calcium and BALP were significantly lower in the OZL group than in the OS group. CONCLUSION: The combination treatment with ZA and letrozole is effective in the inhibition of bone resorption and in the preservation of BMD. Measurement of serum osteocalcin, urine NTX, and BMD, levels are recommended as surrogate markers for determining the response for the treatment of bone loss.
Alkaline Phosphatase ; Animals ; Aromatase Inhibitors ; Biomarkers ; Bone Density ; Bone Resorption ; Breast Neoplasms ; Calcium ; Estrogens ; Female ; Models, Animal ; Osteocalcin ; Ovariectomy ; Rats ; Tibia

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S-phase Fraction as an Independent Prognostic Factor in Invasive Breast Carcinoma -A Study of Long-term Follow-up.

Jin Hae BAE ; Jeong Won BAE ; Sang Uk WOO ; Chul Whan KIM ; Jae Bok LEE ; Gil Soo SON ; Byum Whan KOO

Journal of Breast Cancer.2007;10(1):36-42. doi:10.4048/jbc.2007.10.1.36

PURPOSE: To evaluate the significance of the S-phase fraction (SPF) and DNA ploidy, determined by DNA flow cytometry, as prognostic markers in invasive breast cancer. METHODS: Between October 1986 and June 1999, 143 breast carcinoma patients, treated by surgery, were analyzed. Flow cytometry was performed for the identification of the SPF and DNA ploidy, with immunohistochemistry performed on paraffin embedded material for the hormone receptor. Two SPF classes were defined on the basis of the median value (10) by using a log rank test (high SPF>10, low SPF<10). The correlation between SPF and the clinicopathological factors (tumor size, lymph node status, histological grade and steroid receptor status) and between the SPF and 5 yr disease-free survival (DFS) were investigated. RESULTS: DNA ploidy was not associated with tumor size, lymph node status, histological grade, overall survival and DFS. In a univariate analysis, high SPF values were associated with shorter 5 yr DFS in individual groups. In the node negative group, the 5 yr DFS of the low SPF group was higher than that of the high SPF group, but in the node positive group, the SPF values showed statistical significance with the 5 yr DFS. In a multivariate analysis, the SPF was independently associated with the 5 yr DFS in the node negative group. CONCLUSION: These results suggested the SPF is an independent prognostic factor in lymph node negative, estrogen receptor positive and progesterone receptor negative breast cancers.
Breast Neoplasms* ; Breast* ; Disease-Free Survival ; DNA ; Estrogens ; Flow Cytometry ; Follow-Up Studies* ; Humans ; Immunohistochemistry ; Lymph Nodes ; Multivariate Analysis ; Paraffin ; Ploidies ; Prognosis ; Receptors, Progesterone ; Receptors, Steroid

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The Multidrug Resistance-related Protein and P-glycoprotein Expressions, and the Washout Rates of 99mTc-MIBI in Infiltrating Ductal Carcinoma of Breast, Correlation with the Response After Neoadjuvant Chemotherapy.

Hi Suk KWAK ; Young Tae BAE ; Koon Taek HAN ; In Joo KIM

Journal of Breast Cancer.2007;10(1):29-35. doi:10.4048/jbc.2007.10.1.29

PURPOSE: Numerous non-invasive imaging methods for evaluating the chemotherapy response of breast cancer patients are currently being explored. The aim of present study was to investigate whether the washout rates (WRs) of 99mTc-MIBI could predict the response to chemotherapy in patients suffering with infiltrating ductal carcinoma using the expressions of multidrug resistance-related protein (MRP) and P-glycoprotein (Pgp). METHODS: From May 2002 and March 2004, the patients were randomly and consecutively selected according to the results of immunohistochemical analyses of breast carcinoma specimens before the administration of neoadjuvant chemotherapy. A total 45 infiltrating ductal carcinomas in 45 female patients were selected and they were separated into three groups: group A consisted of tumors with both negative Pgp and MRP expressions (n=15); group B consisted of the tumors that were positive for either a Pgp expression or a MRP expression (n=15); group C consisted of the tumors that were positive for both Pgp and MRP expressions (n=15). All the patients were referred for double phase 99mTc-MIBI mammoscintigraphy after the injection of 925 MBq of 99mTc-MIBI to calculate the WR. The tumor response was evaluated after completion of neoadjuvant chemotherapy. The tumor response was classified as a complete or partial response (the responder group) and stable or progression (the non-responder group). All the patients underwent surgery. RESULTS: The response rate of group C was lower than that of the other groups, but the difference was not statistically significant (p=0.283). The WR of non-responder group was lower than that of the responder group, although the difference was not statistically significant (p=0.674). The washout rates of group C was the highest than other groups and the difference was statistically significant (p=0.001). CONCLUSION: In conclusion, the WR of 99mTc-MIBI is helpful for in vivo determination of both the Pgp and MRP expressions for infiltrating ductal carcinoma of the breast.
Breast Neoplasms ; Breast* ; Carcinoma, Ductal* ; Drug Therapy* ; Female ; Humans ; P-Glycoprotein*

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Prognostic Value of Apoptosis and the Survivin, bcl-2, and p53 Expressions in Breast Cancer Patients.

Myoung Won SON ; Hee Doo WOO ; Doo Min SOHN ; Sang Ho BAE ; Hwa Soo LEE ; Gil Ho KANG ; Sung Yong KIM ; Moo Jun BAEK ; Cheol Wan LIM ; Moon Soo LEE ; Min Hyuk LEE ; Chang Ho KIM ; Tae Yoon KIM ; Young Gi MIN ; Mi Hye OH ; Eui Han KIM ; Chang Jin KIM ; Moo Sik CHO

Journal of Breast Cancer.2007;10(1):19-28. doi:10.4048/jbc.2007.10.1.19

PURPOSE: Survivin is a member of the inhibitor of apoptosis (IAP) protein family, and it is involved in the regulation of cell division. The over-expression of survivin has been reported to be associated with the parameters for a poor prognosis in most human cancers, including lung, breast, colon, stomach, esophagus, pancreas, etc. In this study, we examined the expression of a member of a novel IAP protein family, survivin, in breast cancer and its association with tumor cell apoptosis and the overall prognosis. METHODS: 80 cases of formalin-fixed paraffin-embedded breast cancer tissue were immunostained with, using polyclonal survivin (Novus Biologicals, Littleton, USA), monoclonal bcl-2 (DAKO, Carpinteria, USA), and monoclonal p53 antibodies (DAKO, Carpinteria, USA). The histochemical method used for the analysis of apoptosis was based on ApopTag. Peroxidase In Situ OligoLigation (ISOL) Apoptosis Detection Kit (CHEMICON International Inc. Temecula, USA). RESULTS: Immunohistochemical analysis showed that cytoplasmic survivin expression was positive in 43 of 80 cases (53.8%) of breast carcinomas and it was positive for 70% of the cases that showed a bcl-2 expression tumors. Statistical analysis revealed that the survivin expression was correlated with lymph node metastasis, the tumor stage, and the histological grade. Although the survivin expression was not correlated with p53 mutations, the survivin positive cases were associated with a bcl-2 expression (p=0.015) and a reduced apoptotic index (p=0.024). On the Cox proportional hazard model analysis, the apoptotic index was not identified as a significant independent predictor of overall survival (p=0.072), although the patients with a low apoptotic index (<0.2%) had a worse survival rates than those patient in the group with a high apoptotic index (> or =0.2%). CONCLUSION: The results suggest that apoptosis inhibition of apoptosis by survivin may be a prognostic parameter for a worse outcome in breast carcinoma patients.
Antibodies ; Apoptosis* ; Breast Neoplasms* ; Breast* ; Cell Division ; Colon ; Cytoplasm ; Esophagus ; Humans ; Lung ; Lymph Nodes ; Neoplasm Metastasis ; Pancreas ; Peroxidase ; Prognosis ; Proportional Hazards Models ; Stomach ; Survival Rate

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Prognostic Significance COX-2, VEGF and Cyclin D1 in Distant Metastasis of Breast Cancer.

Jin Sun LEE ; Jeong Hun CHOI

Journal of Breast Cancer.2007;10(1):10-18. doi:10.4048/jbc.2007.10.1.10

PURPOSE: The most important independent prognostic factors of breast cancer have been reported to the tumor size and lymph node metastasis, as well as DNA ploidy, proliferation index, and various receptors, including estrogen receptor (ER) and progesteron receptor (PR) and oncogenes, such as c-erbB-2, and the tumor suppressor gene, p53. However, all these prognostic factors are still unable to exactly estimate distant metastasis for breast cancer. Based on this, our aim was to study for the prognostic factors that associated distant metastasis of breast cancer with cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), which are related to angiogenesis, and Cyclin D1, which participates in cell proliferation in breast cancer. METHODS: A retrospective study was carried out on 95 patients, who has undergone an operation for breast cancer, with or without metastasis between January 1993 and July 2001, at the Department of Surgery, Chungnam National University Hospital. The study was based on the immunohistochemical staining of primary tumors for COX-2, VEGF, Cyclin D1, ER, PR and c-erbB-2, which were obtained from tissue samples of 45 and 50 patients with and with no distant metastatic breast cancer. SPSS for Windows, Version 10.0 was used for the statistical analyses. RESULTS: The expressions of COX-2, VEGF and Cyclin D1 were statistically significant in distant metastatic breast cancer. The clinicopathological parameters associated with distant metastasis were the tumor size and histological grade, and lymph node metastasis, lymphovascular invasion, ER and PR. There were positive correlations between 1) COX-2 and VEGF, 2) COX-2 and Cyclin D1, 3) c-erbB-2 and Cyclin D1 and 4) VEGF and Cyclin D1, COX-2 also had positive relationships with the tumor size and c-erbB-2, VEGF had positive relationships with lymph node metastasis, histological grade and lymphovascular invasion, as well as with ER and PR. The overexpressions of COX-2, VEGF and Cyclin D1 shortened the disease-free survival and survival period. CONCLUSION: The overexpressions of COX-2, VEGF and Cyclin D1 were considered poor prognostic factors for the induction of distant metastasis. Therefore, COX-2, VEGF and Cyclin D1 could be used in the prevention of distant metastasis, and prescribed for the treatment of metastatic breast cancer.
Breast Neoplasms* ; Breast* ; Cell Proliferation ; Chungcheongnam-do ; Cyclin D1* ; Cyclins* ; Cyclooxygenase 2 ; Disease-Free Survival ; DNA ; Estrogens ; Genes, Tumor Suppressor ; Humans ; Lymph Nodes ; Neoplasm Metastasis* ; Oncogenes ; Ploidies ; Retrospective Studies ; Vascular Endothelial Growth Factor A*

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Highlights of 10th St. Gallen Breast Cancer Conference: Systemic Adjuvant Treatment.

Seung Il KIM ; Ho yong PARK

Journal of Breast Cancer.2007;10(1):1-9. doi:10.4048/jbc.2007.10.1.1

The 10th St. Gallen International Conference- Primary Therapy of Early Breast Cancer was held in March 2007. The St. Gallen Conferences has focused on reaching expert consensus for patient treatment selection. Three categories were affirmed by responsiveness of endocrine treatment- endocrine responsive, endocrine responsive uncertain, endocrine non-responsive. Risk assessment will be similar than previous meeting (9th meeting) - low, intermediate, and high risk categories. The Panel recommended that patients be offered endocrine therapy or trastuzumab according to endocrine responsiveness or HER2 status. Chemotherapy offered to patients according to risk assessment. For patients with endocrine responsive and HER2 negative, selection of patient for chemotherapy is major challenge. The Panel of Expert attempted to answer many questions- endocrine therapy, chemotherapy, anti-HER2 therapy, and radiation therapy. This report focused on new information related to the best use of endocrine therapy and chemotherapy.
Breast Neoplasms* ; Breast* ; Congresses as Topic ; Consensus ; Drug Therapy ; Humans ; Risk Assessment ; Trastuzumab

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The Clinical Characteristics and Predictive Factors of Stage IV Breast Cancer at the Initial Presentation: A Review of a Single Institute's Data.

Eun Young KIM ; Seeyoun LEE ; Tae Seok BAE ; Seok Won KIM ; Youngmee KWON ; Eun A KIM ; Jungsil RO ; Eun Sook LEE

Journal of Breast Cancer.2007;10(2):101-106. doi:10.4048/jbc.2007.10.2.101

PURPOSE: The aim of this study is to evaluate stage IV breast cancer at the initial presentation by the review of a single institute' data. We also tried to figure out the factors to predict stage IV breast cancer. METHODS: We reviewed the prospectively collected database of 1,424 consecutive patients with primary breast cancer at the National Cancer Center in Korea from October 2000 to January 2005. RESULTS: The proportion of stage IV breast cancer was 2.7% (38/1,424). The median tumor size of the stage IV patients was 4.1 cm. The most common metastatic site was bone (47.4%) followed by lung (44.7%) and liver (36.8%). Metastases were found in 0.9% (6/672) of the T1 tumors, 2.4% (13/535) of the T2 tumors, 8.3% (4/48) of the T3 tumors, and 27.1% (13/48) of the T4 tumors (p<0.001). On multivariate analysis, the statistically significant predictors of distant metastasis were tumor size (> or =2 cm) (p=0.026), positive lymph node status (p<0.001), alkaline phosphatase (>104 IU/L) (p=0.013), aspartate transferase (>40 IU/L) (p=0.003) and CA15-3 (>32 U/mL) (p=0.025). CONCLUSION: Our study showed that the factors to predict distant metastasis of breast cancer were large size of tumor, positive lymph node status, elevated alkaline phosphatase, aspartate transferase and CA15-3. Therefore breast cancer patients with those clinical characteristics should be carefully evaluated to detect distant metastasis.
Alkaline Phosphatase ; Aspartic Acid ; Breast Neoplasms* ; Breast* ; Humans ; Korea ; Liver ; Lung ; Lymph Nodes ; Multivariate Analysis ; Neoplasm Metastasis ; Prospective Studies ; Transferases

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