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ABSTRACT: The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades.
We examined the characteristics of the tumors treated in three time periods between 1982 and 2010. Estrogen receptor (ER), progesterone receptor (PgR) and HER2 status were assessed by immunohistochemistry. Correlation of hormone receptor levels with clinicopathological factors and prognosis was analyzed in ER-positive, HER2-negative breast cancer in two age groups (≤50 years versus >50 years).
The frequency of ER-positive breast cancer in women aged 50 years or younger increased greatly over the interval studied (1982-1991: 52.5%, 1992-2001: 72.6%, 2002-2010: 87.1%, P < 0.0001). The frequency of ER-positive tumors also significantly increased in women over 50 years of age (1982-1991: 69.4%, 1992-2001: 73.3%, 2002-2010: 78.6%, P = 0.029). In ER-positive, HER2-negative breast cancer, tumor grade was negatively correlated with expression levels of ER and PgR. Prognosis for patients with ER-positive, HER2-negative disease significantly improved over time, due to advances in adjuvant therapies.
It is necessary to establish risk factors, both genetic and environmental, capable of predicting the risk of ER-positive breast cancer and thus enable the efficient selection of candidates for hormone receptor-targeted chemoprevention.
Annals of Oncology 11/2010; 22(6):1318-25. · 6.43 Impact Factor
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ABSTRACT: Constitutively activated signal transducers and activators of transcription (Stats), in particular Stat3 and Stat5, have been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis in various cancers. Stat3 is essential in mammary gland epithelial cell apoptosis and involution, whereas Stat5 is well established as a key factor in mammary epithelial cell growth and differentiation. Crosstalk between Stats and estrogen receptor (ER) has been demonstrated by several laboratories and we have focused on the role of Stat5 in ER-positive breast cancer. Using immunohistochemical techniques, we examined the expression of Stat3 and Stat5 in 517 human breast cancer tissues and analyzed their significance for prognosis and prediction of response to endocrine therapy. Stat5 expression was significantly correlated with histological grade (P<0.0001), ER (P=0.02), and progesterone receptor (P=0.026) expression. There was no difference between Stat3 expression and clinicopathological factors. In 346 patients with ER-positive breast cancer, patients with Stat5 positive tumors had significantly increased overall survival (P=0.0009) in multivariate analysis. There were 70 patients who received endocrine therapy as first-line treatment for metastatic breast cancer at relapse. The patients whose primary breast tumors were Stat5 positive, had significantly better response to endocrine therapy (P=0.04), and longer survival after relapse (P=0.0003), than those whose tumors were Stat5 negative. The present study demonstrates for the first time that Stat5 is a predictive factor for endocrine therapy response and a strong prognostic molecular marker in ER-positive breast cancer. Our data suggest that the expression of Stat5 is helpful in selecting patients who may benefit from endocrine therapy.
Endocrine Related Cancer 09/2006; 13(3):885-93. · 4.36 Impact Factor
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ABSTRACT: AIB1 (amplified in breast cancer 1) is a member of the steroid receptor coactivator family and is a key factor in enhancing estrogen-dependent transcription. To evaluate the clinical significance of AIB1 in breast cancer, we performed Southern blot analysis of the AIB1 gene on 124 human breast cancer tissues. We also performed reverse transcription-polymerase chain reaction and semi-quantitative analysis of AIB1 mRNA expression on 58 of the tissues, and immunohistochemical detection of AIB1 protein on 115 of the tissues. On Southern blot analysis, the AIB1 gene was amplified in only two of the 124 breast cancer cases. On semi-quantitative analysis, the relative expression level of AIB1 normalized to that of GAPDH varied from 0.247 to 7.721 (median = 0.94), and was not correlated with any clinico-pathological factors. Although most of the breast cancer cells revealed cytoplasmic staining of AIB1, only 16% (18 in 115) showed nuclear staining of AIB1 protein. AIB1 nuclear expression was correlated with positivity for estrogen receptor alpha (P = 0.022). Those patients with tumor samples that showed nuclear staining of AIB1 tended to be successfully treated by endocrine therapy in comparison with those who did not show nuclear staining of AIB1. In conclusion, AIB1 nuclear expression was correlated with the estrogen receptor alpha status, and patients with AIB1 nuclear expression tended to be successfully treated by hormonal therapy.
Breast Cancer Research and Treatment 09/2003; 80(3):339-45. · 4.43 Impact Factor
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Y Nakashima,
M Yano,
Y Kobayashi,
S Moriyama,
H Sasaki,
T Toyama, H Yamashita,
I Fukai,
H Iwase,
Y Yamakawa,
Y Fujii
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ABSTRACT: Tumors require ongoing angiogenesis to support their growth. Inhibition of angiogenesis by production of antiangiogenic factors should be a viable approach for cancer gene therapy. In this study, we investigated whether intravenous administration of endostatin gene complexed with a cationic vector (GL67/DOPE or PEI22K) could inhibit the development of lung tumors in mice injected i.v. with NFSa Y83 fibrosarcoma cells (5 x 10(5)) which frequently form lung metastasis. mRNA and protein of the transfected gene were produced in the lung and other organs of the transfected mice as assessed by immunohistochemistry, Western blotting and reverse transcription-polymerase chain reaction. Single intravenous injection of the endostatin gene (60 microg) complexed with either GL67/DOPE or PEI22K on day 3 or day 7 after fibrosarcoma cell inoculation significantly inhibited tumor formation in the lung as evidenced by the reduced number of lung tumors and lung weight, and prolonged survival of the endostatin gene-transfected mice compared with control mice. These findings suggested that the endostatin gene therapy, using cationic vector-mediated intravenous gene transfer, might be a feasible strategy for organ-targeted prevention and regulation of possible disseminated cancers.
Gene Therapy 02/2003; 10(2):123-30. · 3.71 Impact Factor
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ABSTRACT: We addressed the clinicopathological significance of the oestrogen receptor (ER) beta protein, including an ERbeta variant, ERbetacx, in normal human breast and breast cancer. The reverse transcriptase-polymerase chain reaction (RT-PCR) showed that wild-type ERbeta (ERbetaw) mRNA expression was higher in normal than cancer tissues, and that ERbetacx mRNA was higher in cancer than in normal tissues. Immunohistochemistry of 22 normal breast tissues and 57 breast cancers was performed with three different ERbeta antibodies and one ERbetacx antibody. All normal breast samples showed staining with the three ERbeta antibodies, suggesting that ERbetaw might have a physiological role in oestrogen signalling in the normal breast. In breast cancer, expression of the ERbetaw protein correlated well with the expression of the ERalpha and progesterone receptor (PgR), as well as histological grade (HG), and tended to indicate a better prognosis than when ERbetaw was absent. Thirty-one (54%) breast cancer samples contained ERbetacx, whereas the corresponding tissue for normal breast samples stained positive in only two (9%).
European Journal of Cancer 03/2002; 38(3):380-6. · 5.54 Impact Factor
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ABSTRACT: A 38-year-old woman with cancer in the left breast underwent standard radical mastectomy. The estrogen receptor and progesterone receptor status of the primary tumor was unknown. Ten years after the surgery, a metastatic liver tumor was detected, and chemoendocrine therapy, consisting of cyclophosphamide, epirubicin, 5-fluorouracil (CEF) and medroxyprogesterone acetate (MPA) was initiated. The metastatic liver tumor showed a partial response after 11 cycles of such chemoendocrine therapy. Subsequently, MPA alone was given daily as maintenance therapy, and the disease has remained stable for 6 years. For women with metastatic breast cancer, complete remission is uncommon, and stable disease is a reasonable goal of successful therapy. In this respect, chemoendocrine therapy with CEF and MPA, followed by MPA alone as maintenance therapy, was successful in the patient reported here. Importantly, the patient's quality of life has remained favorable for several years after the partial response was achieved.
International Journal of Clinical Oncology 01/2002; 6(6):306-9. · 1.41 Impact Factor
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ABSTRACT: To estimate the clinical value of estrogen receptor (ER) beta expression in breast cancer we used an immunohistochemical method to detect the wild-type ERbeta in 88 primary breast cancers. We used a highly specific polyclonal antibody to the carboxyl terminus of wild-type ERbeta. This antibody reacted with neither other variant forms of ERbeta nor any part of ERalpha. Slides were evaluated on a scale representing the estimated proportion and intensity of positive-staining tumor cells. Positive staining could be seen in 52 (59.1%) of 88 breast cancers; 36 (40.9%) were negative. Although there was no correlation between ERbeta staining and age, node status, tumor size, histological grade, or progesterone receptor (PgR)-enzyme immunoassay (EIA) status, we did observe a significant correlation with ERalpha-EIA (Fisher's exact probability test: P=0.0169). Moreover, ERbeta positive cases showed a better prognosis than negative cases in disease-free survival rate (Logrank test: P=0.0662, Breslow-Gehan-Wilcoxson test: P=0.0318). Our data demonstrated the possibility that wild-type ERbeta protein expression could be used as a good prognostic indicator for breast cancer.
Cancer Letters 03/2001; 163(2):207-12. · 4.24 Impact Factor
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ABSTRACT: To evaluate the efficiency of measuring telomerase activity levels in clinical diagnosis, we performed a semiquantitative analysis of telomerase activity in breast tumors and compared the results with the histological findings. Breast tissue adjacent to areas of cancer were also serially resected and checked for telomerase activity. The amount of telomerase activity in the breast cancers ranged widely, from 0.36 to 1180 units/microg, with 31 of the 34 (91.2%) showing a value above 1.0unit/microg. None of the normal breast tissues including mastopathy, and only 4 (23.5%) of 17 benign breast masses had values above 1.0unit/microg. Telomerase activity was detectable in serial sections of adjacent tissues as far as 10mm from the macroscopic tumor margin with histologically detectable cancer cells. Furthermore, telomerase activity was detectable in the scrape specimens obtained from the stump of the surgical margins for breast-conserving surgery, and this activity was in accordance with the histological findings. These findings show that conducting a semiquantitative assay of telomerase activity is useful for evaluating the surgical margin in breast-conserving surgery.
Surgery Today 02/2001; 31(4):289-94. · 1.22 Impact Factor
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H Iwata,
M Yamamoto,
R Nemori,
M Mizutani,
T Iwase,
S Miura,
Y Obata,
Y Hara,
Y Omoto,
T Toyama, H Yamashita,
H Iwase,
S Kobayashi
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ABSTRACT: Extracellular matrix-degrading proteinases secreted by malignant tumor cells have been thought to play an essential role in the processes of invasion and metastasis. However, existence and localization of gelatinase activity in breast cancer tissues have not been clarified.
We developed a novel film for highly reproducible detection and the localization of gelatinolytic activity. This film has a gelatin layer with a constant thickness 7 microm, and adequate crosslinking to control the speed of degradation by proteases. Cryosections of several breast cancer tissues were put on this gelatin film and incubated for 16 hrs at 37 degrees C. After staining with ponceau 3R dye, the digested area was evaluated under light microscopy.
Digestion of gelatin was detected in more than 90%of breast cancer specimens, although it varied in degree and area for each case. In most cases, the gelatinolytic activity was located within cancer nests, and was not detected in stromal cells surrounding cancer cells. The gelatinolytic activity was inhibited by 1,10-phenanthroline, an inhibitor of matrix metalloproteinases (MMPs).
In this study, the localization of net MMP activity was confirmed in breast cancer nest using film in situ zymography. Detailed analysis on the relationship between the strength or distribution of MMP activity and malignancy are anticipated in the future.
Breast Cancer 02/2001; 8(2):111-5. · 1.36 Impact Factor
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Y Ando,
H Iwase,
S Ichihara,
S Toyoshima,
T Nakamura, H Yamashita,
T Toyama,
Y Omoto,
S Karamatsu,
S Mitsuyama,
Y Fujii,
S Kobayashi
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ABSTRACT: To investigate the alterations of genetic instabilities in carcinogenesis of the breast, we analyzed the allelotypic profile of 65 ductal carcinomas in situ (DCIS), compared with that of 207 invasive ductal carcinomas (IDC) of the breast. These studies were performed by means of examining microsatellite-length polymorphisms at seven loci (AluVpa, ESR, D11S988, D13S267, D16S398, D17S1159, and D17S855) from microdissected paraffin sections. Allelic loss or imbalance, considered a loss of heterozygosity (LOH), tended to be more frequently seen in IDC than in DCIS. In particular, the frequency of LOH at the 17p locus was significantly higher in IDC than in DCIS (42 vs. 23%, P=0.022). LOH in DCIS was most frequently seen at D16S398 (26%). LOH frequency at D16S398 in low- and intermediate-grade DCIS was higher than that in high-grade DCIS, while LOH frequencies at D11S988 and D17S1159 in low- and intermediate-grade DCIS was lower than those in high-grade DCIS. LOH frequency at D11S988 in non-comedo type DCIS was lower than that in comedo type DCIS. Furthermore, the frequency of microsatellite instability (MSI) at only one locus in DCIS (28%) was statistically higher than that in IDC (6%) (P<0.001), while there was no difference between the frequency of MSI at multiple loci in DCIS (6%) and that in IDC (3%). Together, these observations indicate that chromosomal losses of 16q may occur in low- and intermediate-grade DCIS and those of 11p and 17p may occur high-grade DCIS, and that MSI occurring at only one locus is not yet clear and MSI at multiple loci is uncommon in not only IDC but also DCIS of the breast.
Cancer Letters 09/2000; 156(2):207-14. · 4.24 Impact Factor
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ABSTRACT: Previous series concerning tamoxifen (TAM) rechallenge did not obtain satisfactory results. Using stricter criteria, we now assess the usefulness of readministration of TAM as an initial therapy for patients with recurrent breast cancer.
The eligibility criteria were postmenopausal, estrogen receptor (ER) positive or unknown, at least 12 months of adjuvant TAM, a 6-month or longer drug-free period and no previous therapy after recurrence. A total of 10 patients were enrolled. TAM was administered in daily doses of 20 or 30 mg.
The mean age of the patients at the time of recurrence was 64.8 years. The receptor status was positive in 8 patients and unknown in 2. The median disease-free interval (DFI) after mastectomy was 71.7 months. A complete response was observed in one patient, a partial response in 6, stable disease in 2, and progression in one. The response rate was thus 70%, with an additional two patients showing no progression over 6 months. Although only one patient with a DFI of less than 48 months showed a positive response, all patients with a DFI longer than 48 months showed a clinical response. The duration of response was less than 12 months in 3 patients and longer in 4.
The post-adjuvant readministration of tamoxifen is a useful first choice therapy for postmenopausal recurrent breast cancer patients with positive ER and longer DFI.
Breast Cancer 02/2000; 7(2):149-52. · 1.36 Impact Factor
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ABSTRACT: The overexpression of c-erbB-2 protein (ErbB2), epidermal growth factor receptor (EGFR), and/or cathepsin D (CD) in breast cancer is known to be a poor prognostic factor. Eighty frozen breast cancer specimens obtained at the initial operation were examined for ErbB2, EGFR, and CD by immunohistochemical assay (ICA) and enzyme immunoassay (EIA). Estrogen and progesterone receptors (ER and PgR) were measured simultaneously by EIA. The mean values +/- 1SD for ErbB2, EGFR and CD were 141 +/- 400 U/mg membrane protein (range: 0-3385), 4.88 +/- 4.33 fmol/mg membrane protein (range: 0-21.1), and 47.1 +/- 32.8 pmol/mg cytosol protein (range: 4.7-182), respectively. The percentage of specimens positive for ErbB2, EGFR, and CD was 12.5, 38.8, and 35%, when the tentative cutoff value were used as 200 U/mg protein, 5 fmol/mg protein, and 50 pmol/mg protein, respectively. These E1A results were correlated with ICA, EGFR and ER were negatively correlated. Although the prognostic value of ErbB2 and EGFR was superior to hormone receptors, ErbB2 and EGFR were interior as predictors compared with lymph node involvement and tumor size. Quantitation of ErbB2, EGFR, and CD can be performed readily using the same specimen in which hormone receptors are measured.
Cancer Detection and Prevention 02/1997; 21(1):29-35. · 2.52 Impact Factor
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ABSTRACT: The expression of estrogen receptor (ER) and bcl-2 (Bcl-2), an apoptosis protective oncogene, in normal and cancerous breast duct epithelia was immunohistochemically examined in fresh frozen tumor tissues from 142 Japanese breast cancer patients. The clinico-pathological characteristics and the disease free survival of the patients were analyzed. The expression of both the proteins was also observed in intraductal components of breast cancer. Although less than 1% of normal duct epithelia expressed ER, Bcl-2 was diffusely expressed. The expression of both these proteins in breast cancer significantly correlated with each other. Their expression significantly correlated negatively with tumor size but not with lymph node status. The papillo-tubular sub-type of invasive ductal carcinoma expressed Bcl-2 significantly more frequently than the solid-tubular sub-type. Patients with Bcl-2 expressing tumors survived without recurrence significantly more than those with tumors exhibiting reduced expression. Papillary-cribriform type intraductal components expressed both those proteins more often than the solid-comedo type.
Breast Cancer Research and Treatment 02/1997; 42(2):173-81. · 4.43 Impact Factor
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T Toyama,
H Iwase, H Yamashita,
H Iwata,
T Yamashita,
K Ito,
Y Hara,
M Suchi,
T Kato,
T Nakamura,
S Kobayashi
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ABSTRACT: Human breast-cancer specimens from 100 patients were analyzed for microsatellite instability (referred to as replication error; RER) at 12 genomic loci on 7 chromosomes, and results were correlated with clinicopathologic characteristics. In 42 of 100 breast-cancer patients, we investigated whether RER was associated with the amplification of oncogenes and/or suppression of tumor-suppressor genes. Of the 100 patients, 8 (8%) were RER-positive at one or more chromosomal loci. The majority of RER-positive patients had early-stage disease with ER-positive tumors, suggesting that RER occurs early in breast tumorigenesis. However, no significant correlation was observed between RER and oncogenes or tumor-suppressor genes. Thus, the mechanism of RER in sporadic human breast cancer may be independent of the multi-step carcinogenesis caused by the alterations of oncogenes and tumor-suppressor genes.
International Journal of Cancer 12/1996; 68(4):447-51. · 5.44 Impact Factor
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ABSTRACT: Cathepsin D was assayed in 74 primary breast cancer specimens by enzyme immunoassay (EIA) and immunohistochemical assay (ICA). Of the 74 specimens, 38 (51.4%) were scored positive by ICA, and 25 (33.8%) were scored positive by EIA. The coincidence rate between ICA and EIA was 71.6% (53/74). There was no significant correlation between cathepsin D and menopausal status, tumor size, number size, number of metastatic lymph nodes, histological type of the tumor, or steroid receptor status. Cathepsin D status designated by EIA or ICA predicted neither disease-free survival (DFS) nor overall survival (OAS). Subject analysis with estrogen receptor, menopausal, and lymph node status revealed no association between cathepsin D and DFS or OAS. Therefore, cathepsin D is not an independent prognostic factor in breast cancer.
Journal of Surgical Oncology 01/1996; 60(4):221-6. · 2.10 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFr) levels were analyzed in 140 primary breast cancer specimens by immunohistochemical assay (ICA), competitive binding assay (BA), or enzyme immunoassay (EIA). Thirty-nine of 118 specimens (33.1%) were scored as positive by ICA, 30 of 116 (25.9%; cut-off level 10 fmol/mg protein) by BA, and 31 of 80 (38.9%: cut-off level 5 fmol/mg protein) by EIA. Agreement on EGFr status was 72.3% (68/94) between ICA and BA, 77.0% (57/74) between BA and EIA, and 73.8% (59/80) between EIA and ICA. These discrepancies are based on assay differences and the heterogeneous distribution of cancer cells within specimens. Regardless of the assay method used, EGFr status had a significantly negative correlation with estrogen receptor status. Although EGFr-ICA and BA status had no relationship with prognosis, patients with medium and high EGFr-EIA level tumors (over 5 fmol/mg protein) had shorter relapse-free periods than those with low level tumors. However, the prognostic value of positive EGFr-EIA status was weaker than that of c-erbB-2 overexpression.
Breast Cancer Research and Treatment 01/1994; 28(3):215-21. · 4.43 Impact Factor
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ABSTRACT: Oncogenes (c-erbB-2, c-myc, and some genes linked to the 11q13 lesion), tumor suppressor genes (retinoblastoma gene, p53) and an antimetastatic gene (nm23/nucleoside diphosphate kinase) play important roles in breast cancer progression. Amplification of c-erbB-2, c-myc, and int-2, and expression of RB, p53(mutant), and NDP kinase were determined in 77 primary breast cancer specimens. nm23-H1 allelic loss was also studied. c-erbB-2 and c-myc amplification, loss of RB expression, p53(mutant) expression, and nm23-H1 allelic loss were also found in non-invasive carcinoma. int-2 amplification was significantly correlated with lymph node status (P = 0.02) and a significant association was found between p53(mutant) expression and tumor size (P = 0.04). c-erbB-2 amplification was strongly associated with disease-free and overall survival in multivariate analysis (P = 0.002). All of the c-erbB-2 amplified cases and all but one of the int-2 amplified cases in node-positive patients had relapsed within 2 years post resection. The cancer cells may acquire new proliferative pathways sequentially as a result of multiple genetic alterations which enable them to bypass the estrogen-dependent proliferation.
Japanese journal of cancer research: Gann 09/1993; 84(8):871-8.
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ABSTRACT: Expression of the c-erbB-2 oncoprotein (ErbB-2) and the nm23 anti-metastatic gene product (nucleoside diphosphate [NDP] kinase) was examined in the intraductal and invasive components of 63 fresh human breast cancer tissues. The expression of estrogen receptor (ER) as a marker of hormone dependency and the Ki-67 protein as a proliferative cell marker was also examined. ErbB-2 and ER were positive in 77.8% (28/36) and 64.7% (22/34) of the intraductal components, and in 43.6% (27/62) and 57.1% (36/63) of the invasive components, respectively. NDP kinase was positive in 58% (18/31) of intraductal, and in 30.9% (17/55) of invasive areas. The average Ki-67-positive cell rates were 5.9% in the intraductal, and 10.7% in the invasive components. Thus, the cells within the intraductal component of breast cancer appear to have different characteristics from the invasive component, not only in markers of proliferative ability, but also in the expression of oncogenes and hormone receptors.
Japanese journal of cancer research: Gann 09/1992; 83(8):859-65.
