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1.
J Exp Bot ; 70(19): 5287-5297, 2019 10 15.
Article in English | MEDLINE | ID: mdl-31257443

ABSTRACT

Leaves within crop canopies experience variable light over the course of a day, which greatly affects photosynthesis and crop productivity. Little is known about the mechanisms of the photosynthetic response to fluctuating light and their genetic control. Here, we examined gas exchange, metabolite levels, and chlorophyll fluorescence during the photosynthetic induction response in an Oryza sativa indica cultivar with high yield (Takanari) and a japonica cultivar with lower yield (Koshihikari). Takanari had a faster induction response to sudden increases in light intensity than Koshihikari, as demonstrated by faster increases in net CO2 assimilation rate, stomatal conductance, and electron transport rate. In a simulated light regime that mimicked a typical summer day, the faster induction response in Takanari increased daily CO2 assimilation by 10%. The faster response of Takanari was explained in part by its maintenance of a larger pool of Calvin-Benson cycle metabolites. Together, the rapid responses of electron transport rate, metabolic flux, and stomatal conductance in Takanari contributed to the greater daily carbon gain under fluctuating light typical of natural environments.


Subject(s)
Light , Oryza/metabolism , Photosynthesis , Plant Leaves/metabolism , Oryza/growth & development , Oryza/radiation effects , Plant Leaves/radiation effects
2.
Sci Rep ; 9(1): 7610, 2019 05 20.
Article in English | MEDLINE | ID: mdl-31110228

ABSTRACT

The stomatal density (SD) can be a promising target to improve the leaf photosynthesis in soybeans (Glycine max (L.) Merr). In a conventional SD evaluation, the counting process of the stomata during a manual operation can be time-consuming. We aimed to develop a high-throughput technique for evaluating the SD and elucidating the variation in the SD among various soybean accessions. The central leaflet of the first trifoliolate was sampled, and microscopic images of the leaflet replica were obtained among 90 soybean accessions. The Single Shot MultiBox Detector, an algorithm for an object detection based on deep learning, was introduced to develop an automatic detector of the stomata in the image. The developed detector successfully recognized the stomata in the microscopic image with high-throughput. Using this technique, the value of R2 reached 0.90 when the manually and automatically measured SDs were compared in the 150 images. This technique discovered a variation in SD from 93 ± 3 to 166 ± 4 mm-2 among the 90 accessions. Our detector can be a powerful tool for a SD evaluation with a large-scale population in crop species, accelerating the identification of useful alleles related to the SD in future breeding programs.


Subject(s)
Genetic Variation/genetics , Glycine max/genetics , Algorithms , Alleles , Breeding/methods , Deep Learning , Genotype , High-Throughput Screening Assays/methods , Photosynthesis/genetics , Plant Leaves/genetics , Plant Stomata/genetics
3.
Breast Cancer ; 22(3): 308-16, 2015 May.
Article in English | MEDLINE | ID: mdl-23771556

ABSTRACT

BACKGROUND: Recent studies have indicated that the response to chemotherapy and the prognostic impact of a pathological complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. Predictors of response to chemotherapy and prognostic factors for survival might be different in estrogen receptor (ER)-positive breast cancer. METHODS: Women with Stage II to III ER-positive HER2-negative breast cancer treated with anthracycline and taxane-containing neoadjuvant chemotherapy between 2003 and 2011 were retrospectively analyzed. Expression of forkhead box A1 (FOXA1), B cell lymphoma 2 (BCL2) and microtubule-associated protein tau (MAPT) as well as ER, progesterone receptor, HER2 and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Factors predictive of response to neoadjuvant chemotherapy and distant disease-free survival were analyzed. RESULTS: Tumor grade was positively correlated with Ki67 expression. Expression levels of ER were positively correlated with expression levels of HER2, BCL2, FOXA1 and MAPT in pre-treatment tumors. The Ki67 labeling index was the only factor that was significantly associated with clinical response measured by the reduction of tumor volume and pCR. Lymph node status, expression of ER before neoadjuvant chemotherapy and expression of FOXA1 after neoadjuvant chemotherapy were significantly associated with distant disease-free survival, both by univariate and multivariate analyses. CONCLUSIONS: Patients with ER-positive HER2-negative breast cancer should be selected for neoadjuvant chemotherapy. FOXA1 expression could be a prognostic marker in ER-positive breast cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Hepatocyte Nuclear Factor 3-alpha/metabolism , Neoadjuvant Therapy , Neoplasm Recurrence, Local/metabolism , Adult , Aged , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Retrospective Studies , Survival Rate , tau Proteins/metabolism
4.
Breast Cancer ; 19(4): 302-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22711317

ABSTRACT

The fact that reproductive factors have significant influence on the risk of breast cancer is well known. Early age of first full-term birth is highly protective against late-onset breast cancers, but each pregnancy, including the first one, increases the risk of early-onset breast cancer. Estradiol and progesterone induce receptor activator of NF-kappa B ligand (RANKL) in estrogen receptor (ER)- and progesterone receptor (PgR)-positive luminal cells. RANKL then acts in a paracrine fashion on the membranous RANK of ER/PgR-negative epithelial stem cells of the breast. This reaction cascade is triggered by chorionic gonadotropin during the first trimester of pregnancy and results in the morphological and functional development of breast tissue. On the other hand, the administration of non-steroidal anti-inflammatory drugs in the early steps of weaning protects against tumor growth through reduction of the acute inflammatory reaction of post lactation remodeling of breast tissue. This is experimental evidence that may explain the short-term tumor-promoting effect of pregnancy. The protective effect of prolonged breast feeding may also be explained, at least in a part, by a reduced inflammatory reaction due to gradual weaning. Delay of first birth together with low parity and short duration of breast feeding are increasing social trends in developed countries. Therefore, breast cancer risk as a result of reproductive factors will not decrease in these countries in the foreseeable future. In this review, the significance of reproductive history with regard to the risk of breast cancers will be discussed, focusing on the age of first full-term birth and post lactation involution of the breast.


Subject(s)
Breast Feeding , Breast Neoplasms/etiology , Breast Neoplasms/metabolism , Reproductive History , Breast Neoplasms/epidemiology , Female , Humans , Maternal Age , Pregnancy , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Risk Factors
6.
Int J Clin Oncol ; 16(5): 512-8, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21431343

ABSTRACT

BACKGROUND: Aromatase inhibitors have played a central role in endocrine therapy for estrogen receptor (ER)-positive breast cancer in postmenopausal women. However, many breast cancer patients with tumors expressing ER are unresponsive to aromatase inhibitors, and all patients with advanced disease eventually develop resistance to the therapy. METHODS: Twenty-one postmenopausal women with Stage II to IV breast cancer were treated with aromatase inhibitors as first-line endocrine therapy without surgery. Expression levels of ER, progesterone receptor, HER2 and Ki67 were examined by immunohistochemistry, and correlations between response and duration of the therapy and these levels were analyzed. RESULTS: Patients whose tumors contained two thirds or more ER-positive cells effectively responded to aromatase inhibitors (P = 0.006) and displayed longer time to progression during first-line endocrine therapy (P = 0.003) and longer time to endocrine therapy failure (P = 0.02). Patients whose tumors showed less than 15% Ki67 labeling index also displayed longer time to progression (P = 0.003). CONCLUSION: High ER expression and low Ki67 expression were associated with improved time to progression with aromatase inhibitors as first-line endocrine therapy. Our findings will be helpful when endocrine therapy is planned in either early stage or advanced breast cancer.


Subject(s)
Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Ki-67 Antigen/metabolism , Neoplasms, Hormone-Dependent/drug therapy , Receptors, Estrogen/metabolism , Aged , Aged, 80 and over , Biomarkers, Pharmacological/metabolism , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Hormone Replacement Therapy , Humans , Ki-67 Antigen/genetics , Middle Aged , Neoplasm Staging , Postmenopause , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptors, Estrogen/analysis , Receptors, Estrogen/genetics , Receptors, Progesterone/genetics , Receptors, Progesterone/metabolism
7.
Chin Med J (Engl) ; 122(15): 1764-8, 2009 Aug 05.
Article in English | MEDLINE | ID: mdl-19781322

ABSTRACT

BACKGROUND: Estrogen receptor alpha (ER alpha) is the most important endocrine therapy responsiveness predictor for women with breast cancer. The accuracy of the prediction of the response to endocrine therapy was thought to be affected by involving the estrogen receptor coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. Nuclear corepressor 1 (NCOR1) is one of the ER a transcription repressor. The objective of the study is to investigate the expression of NCOR1 at the protein level and pursue its predictive value for breast cancer endocrine therapy. METHODS: In the present study, the level of expression of NCOR1 protein has been assessed by immunohistochemistry in 104 cases of invasive carcinoma of the breast. Associations between NCOR1 protein expression and different clinicopathological factors and survival were sought. RESULTS: It was found that NCOR1 was expressed at significantly higher levels in responsive patients treated with endocrine therapy as first-line treatment on relapse. Responsive patients also had a significantly longer post-relapse survival and overall survival. No NCOR1 expression difference was found between patient by age, tumor size, lymph node status, different histological grade groups and human epidermal growth factor receptor 2 (HER2) status. Multivariate analysis showed that NCOR1 is an independent prognostic factor for over-all survival. CONCLUSIONS: In breast cancer, NCOR1 protein expression level predicts response to endocrine therapy as first-line treatment for breast cancer patients on relapse and NCOR1 protein level assay may increase the accuracy in the endocrine treatment determination and, therefore, improving the patients survival.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Nuclear Receptor Co-Repressor 1/metabolism , Antineoplastic Agents, Hormonal/therapeutic use , Estrogen Receptor alpha/metabolism , Female , Gene Expression Regulation , Humans , Immunohistochemistry , Middle Aged , Receptor, ErbB-2/metabolism , Receptors, Progesterone/metabolism , Tamoxifen/therapeutic use
8.
Cancer Sci ; 100(11): 2028-33, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19659610

ABSTRACT

Endocrine therapy is the most important treatment of choice for estrogen receptor (ER)-positive breast cancer. Potential mechanisms for resistance to endocrine therapy involve ER-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine therapy resistance, particularly resistance to aromatase inhibitors, have not been clearly established. Sixteen postmenopausal patients with ERalpha-positive primary breast cancer were treated daily with 25 mg of exemestane (an aromatase inhibitor) for 6 months. Expressions of ERalpha, ERbeta, progesterone receptor (PgR), androgen receptor (AR), amplified in breast cancer 1 (AIB1), aromatase, epidermal growth factor receptor, human epidermal growth factor receptor type 2, Ki67, cyclin D1, p53, Bcl2, signal transducer and activator of transcription 5 (Stat5), and insulin-like growth factor binding protein 5 (IGFBP5), and phosphorylations of ERalpha serine (Ser) 118, ERalpha Ser167, Akt Ser473, and p44/42 MAPK threonine (Thr) 202/tyrosine (Tyr) 204, were examined by immunohistochemistry on pretreatment tumor biopsies and post-treatment surgical specimens. Analyses were made to test for correlations with response to exemestane. Of the 16 patients, seven responded and nine retained stable disease. High-level expression of AIB1 and phosphorylation of Akt Ser473 were significantly associated with a better response to exemestane, suggesting that these factors could be considered as predictors of exemestane response. Expressions of ERalpha, ERbeta, PgR, aromatase, Ki67, cyclin D1, and p53, and phosphorylations of ERalpha Ser118, ERalpha Ser167, and p44/42 MAPK Thr202/Tyr204, were decreased, whereas expressions of Stat5 and IGFBP5 were increased in post-treatment specimens compared to the values in pretreatment biopsies. Thus, the analysis of factors involved in the estrogen-dependent growth-signaling pathways may be useful in identifying patients responsive to exemestane.


Subject(s)
Androstadienes/therapeutic use , Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Histone Acetyltransferases/analysis , Receptors, Estrogen/analysis , Trans-Activators/analysis , Aged , Aged, 80 and over , Breast Neoplasms/chemistry , Estrogen Receptor alpha/analysis , Estrogen Receptor beta/analysis , Female , Humans , Immunohistochemistry , Ki-67 Antigen/analysis , Nuclear Receptor Coactivator 3 , Phosphorylation , Receptors, Progesterone/analysis
9.
Nicotine Tob Res ; 10(8): 1391-5, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18686187

ABSTRACT

All forms of tobacco cause cardiovascular disease, and tobacco-related disease is a leading cause of death worldwide. Smoking oxidizes low-density lipoprotein (LDL) particles, and oxidized LDL particles are thought to play an early and critical role in atherosclerogenesis. Hyper-low-density lipoproteinemia is one of the risk factors for cardiovascular disease, but small, dense LDL particles have been associated with an increased risk for cardiovascular disease. Small, dense LDL correlates with some cardiovascular risk factors such as diabetes mellitus, hypertriglyceridemia, hypo-high-density lipoproteinemia, and hypertension. Although smoking is also a major risk factor for cardiovascular disease, the relationship between smoking and small, dense LDL particles has not been described previously. Our cross-sectional study examined this relationship in a population of 18 healthy young adult men (9 smokers and 9 never-smokers, aged 21-24 years) from the same college. Concentrations of blood lipids and the LDL migration index (LDL-MI) were examined. Although concentrations of blood lipids did not differ between smokers and never-smokers, the LDL-MI had a strong tendency to be lower in smokers. The LDL-MI is larger in the presence of a greater proportion of small, dense LDL particles. These results indicate that tobacco smoking is associated with a decrease in the proportion of small, dense LDL particles. Regardless of these surprising results, we do not recommend smoking, given that it is a major cause of cardiovascular disease.


Subject(s)
Biomarkers/blood , Lipoproteins, LDL/blood , Smoking/blood , Cross-Sectional Studies , Female , Humans , Japan , Male , Oxidation-Reduction , Reference Values , Young Adult
10.
Endocr Relat Cancer ; 15(3): 755-63, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18550720

ABSTRACT

Endocrine therapy has become the most important treatment option for women with estrogen receptor (ER)-positive breast cancer. Urgently needed are prognostic assays that can identify those who need additional adjuvant therapy, such as signal transduction inhibitors or chemotherapy, for ER-positive early breast cancer. We examined phosphorylation of ERalpha serine (Ser) 118, ERalpha Ser167, p44/42 mitogen-activated protein kinase (MAPK), and Akt and expression of progesterone receptor, amplified in breast cancer 1 (AIB1), human epidermal growth factor receptor 2 (HER2), p53, and Ki67 in ER-positive breast cancers by immunohistochemistry, and analyzed their significance for prognosis. Phosphorylation levels of ERalpha Ser118, ERalpha Ser167, MAPK, and Akt were positively correlated. AIB1 expression was significantly associated with phosphorylation of ERalpha Ser118, MAPK, and Akt, and HER2 expression. Low phosphorylation of ERalpha Ser118 and high phosphorylation of ERalpha Ser167 were associated with significantly improved disease-free (P=0.0003 and P=0.0002 respectively) and overall survival (P=0.0007 and P=0.0016 respectively) in multivariate analyses. Our data suggest that phosphorylation of ERalpha Ser118 and ERalpha Ser167 affects survival in ER-positive breast cancer and could be helpful in distinguishing patients who are likely to benefit from endocrine therapy alone from those who are not.


Subject(s)
Breast Neoplasms/mortality , Carcinoma, Ductal, Breast/mortality , Estrogen Receptor alpha/metabolism , Protein Serine-Threonine Kinases/metabolism , Serine/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Hormonal/therapeutic use , Biomarkers, Tumor/metabolism , Breast Neoplasms/diagnosis , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/diagnosis , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast/metabolism , Estrogen Receptor alpha/chemistry , Female , Follow-Up Studies , Humans , Middle Aged , Phosphorylation , Prognosis , Survival Analysis , Treatment Outcome
11.
Breast Cancer ; 15(2): 153-8, 2008.
Article in English | MEDLINE | ID: mdl-18311481

ABSTRACT

Subtyping of breast cancers by means of DNA microarray analyses has given rise to the new concept of the basal-like subtype; this subtype is in effect the equivalent of so-called "triple-negative" breast cancer. Basal-like breast cancer has aggressive characteristics, such as high histological grade, mutation of the TP53 gene, and negative hormone receptors. It tends to occur in relatively young women and is highly correlated with suppression of BRCA1 function. The EGFR gene is often overexpressed in this subtype. Here, research carried out in the last few years into the basal-like subtype of breast cancer will be reviewed.


Subject(s)
Breast Neoplasms/pathology , Neoplasms, Basal Cell/pathology , Breast Neoplasms/genetics , ErbB Receptors/genetics , Female , Genes, BRCA1/physiology , Humans , Mutation/genetics , Neoplasms, Basal Cell/genetics , Tumor Suppressor Protein p53/genetics
12.
Jpn J Clin Oncol ; 37(11): 820-8, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17932113

ABSTRACT

BACKGROUND: The clinical value of estrogen receptor (ER) beta and its variants has been investigated. However, reported results have frequently been discordant. METHODS: We investigated mRNA and protein expression of ERbeta wild type (ERbeta1) and its variant, ERbetacx/beta2, by quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry in 150 breast cancer tissues, and analyzed association between their expression and clinicopathological factors and prognosis. RESULTS: ERbeta1 mRNA expression was significantly correlated with progesterone receptor expression and low histological grade. ERbeta1 protein expression was significantly correlated with small tumor size, negative lymph node status and low histological grade. ERbetacx/beta2 protein expression was significantly correlated with ERalpha expression and low histological grade. Patients with high expression of ERbeta1 or ERbetacx/beta2 had a significantly better disease-free and overall survival than those with low expression. In multivariate analysis, ERbetacx/beta2 mRNA expression was identified as a prognostic factor in disease-free and overall survival. CONCLUSION: Our results indicate that ERbetacx/beta2 mRNA expression is an independent prognostic factor in breast cancer. ERbeta expression status, both wild-type and the variant cx/beta2, might represent significant predictors of breast cancer prognosis.


Subject(s)
Breast Neoplasms/metabolism , Estrogen Receptor beta/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Humans , Immunohistochemistry , Middle Aged , Prognosis , Protein Isoforms , RNA, Messenger , Reverse Transcriptase Polymerase Chain Reaction , Survival Analysis
13.
Jpn J Clin Oncol ; 37(8): 575-82, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17675285

ABSTRACT

BACKGROUND: Expression of estrogen-regulated genes has been considered as potential predictive markers for endocrine therapy. We focused on two insulin-like growth factor binding proteins (IGFBPs): IGFBP-4, which is an early-responsive estrogen-induced gene, and IGFBP-5, which is an estrogen-repressed gene. Investigation of IGFBP-4 and IGFBP-5 expression would provide important information for predicting prognosis and endocrine responsiveness. METHODS: The levels of IGFBP-4 and IGFBP-5 mRNA expression in 162 human breast cancer tissues were analyzed using quantitative real-time reverse transcriptase-PCR. The association between IGFBP-4 and IGFBP-5 expression and clinicopathological factors was then analyzed. RESULTS: The levels of IGFBP-4 and IGFBP-5 mRNA expression were positively correlated with estrogen receptor (ER) and progesterone receptor (PgR) status and were negatively correlated with HER2 overexpression. Patients with a high level of IGFBP-4 mRNA expression had better disease-free and overall survival than those with a low expression. Multivariate analysis showed that IGFBP-4 mRNA expression is an independent prognostic factor for disease-free survival. When analyzed in 116 patients with ER-positive breast cancer, patients whose tumor expressed higher levels of IGFBP-4 mRNA or lower levels of IGFBP-5 mRNA had better disease-free survival. CONCLUSION: IGFBP-4 mRNA expression was an independent prognostic factor in breast cancer, and patients with ER-positive breast cancer whose tumor expressed higher levels of IGFBP-4 and lower levels of IGFBP-5 had a better prognosis than those without such findings.


Subject(s)
Breast Neoplasms/mortality , Insulin-Like Growth Factor Binding Protein 4/genetics , Insulin-Like Growth Factor Binding Protein 5/genetics , Adult , Aged , Aged, 80 and over , Breast Neoplasms/chemistry , Breast Neoplasms/genetics , Disease-Free Survival , Female , Gene Expression , Humans , Middle Aged , Polymerase Chain Reaction , Prognosis , RNA, Messenger/analysis , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis
14.
Breast Cancer ; 13(4): 334-9, 2006.
Article in English | MEDLINE | ID: mdl-17146158

ABSTRACT

BACKGROUND: It has been reported that 5'-deoxy-5-fluorouridine (5'-DFUR), the pro-drug of 5-FU, is effective treatment for breast cancer that express thymidine phosphorylase (dThdPase). Since oral cyclophosphamide (CPA) induces dThdPase, a synergistic effect can be expected by combining CPA with 5'-DFUR. We evaluated the usefulness of combination chemotherapy using CPA and 5'-DFUR in patients with relapsed breast cancer in this prospective phase II study. METHODS: Patients with relapsed, advanced breast cancer with evaluable lesions were given 5'-DFUR at 800 mg/day/body and CPA at 100 mg/day/body for 2 weeks, then underwent 2 weeks of drug withdrawal. This was considered one course of treatment. It was repeated until progressive disease (PD) was confirmed. The lesions were evaluated according to UICC criteria and compared with regard to the clinical status. RESULTS: Sixty-four patients with relapsed, advanced breast cancer were registered. Complete response (CR) was seen in 7 patients, partial response (PR) in 12 patients, no change (NC) in 25 patients, of whom 11 achieved long NC with the effect lasting for more than 6 months, and PD was seen in 20 patients. The response rate was 29.7%. The total number of CR, PR, and long NC cases was 30, which comprise-46.9% of the total 64 cases (the clinical benefit rate). As for adverse events, hematological toxicities were seen in 9 patients, with grade 3 toxicits was seen in 1 patient. All other adverse events were grade 1 or 2. CONCLUSION: For those patients who achieved an effect more than NC, it was possible to continue the therapy for an average of 53 weeks. This treatment method is worth considering for patients who have metastatic breast cancer, that is not life threatening.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cyclophosphamide/administration & dosage , Floxuridine/administration & dosage , Administration, Oral , Adult , Aged , Breast Neoplasms/mortality , Female , Humans , Middle Aged , Prospective Studies , Treatment Outcome
15.
Breast Cancer Res ; 8(4): R48, 2006.
Article in English | MEDLINE | ID: mdl-16869955

ABSTRACT

INTRODUCTION: Endocrine therapy is the most important treatment option for women with hormone receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified. MATERIALS AND METHODS: The expression of HER2, p53, and Ki67 was examined by immunohistochemistry in primary breast tumour specimens from 73 metastatic breast cancer patients who received first-line treatment with endocrine therapy on relapse, and analysed to determine whether expression of these molecular markers affected the response to endocrine therapy. RESULTS: Of the 73 invasive ductal carcinomas, 12.3%, 21.9%, and 35.6% were positive for HER2 overexpression, p53 protein accumulation, and Ki67 expression, respectively. All patients received endocrine therapy as first-line treatment for metastatic breast cancer; 34 patients (46.6%) responded. Patients with primary breast tumours that had p53 protein accumulation and Ki67 expression showed significantly more resistance to endocrine therapy (P = 0.0049 and P = 0.024, respectively). There were also tendencies for HER2 overexpression to correlate with resistance to endocrine therapy, but this did not reach significance. p53 protein accumulation and HER2 overexpression significantly reduced post-relapse survival (P < 0.0001 and P = 0.001, respectively), and these factors were also statistically significant in a multivariate analysis. CONCLUSION: These data suggest that p53 protein accumulation is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in hormone receptor-positive metastatic breast cancer.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/physiopathology , Carcinoma, Ductal, Breast/physiopathology , Drug Resistance, Neoplasm , Tumor Suppressor Protein p53/biosynthesis , Adult , Aged , Breast Neoplasms/mortality , Breast Neoplasms/secondary , Breast Neoplasms/therapy , Carcinoma, Ductal, Breast/mortality , Carcinoma, Ductal, Breast/secondary , Carcinoma, Ductal, Breast/therapy , Female , Genes, erbB-2/physiology , Humans , Ki-67 Antigen/biosynthesis , Middle Aged , Predictive Value of Tests , Prognosis , Survival Analysis
16.
Breast Cancer ; 13(1): 74-83, 2006.
Article in English | MEDLINE | ID: mdl-16518065

ABSTRACT

BACKGROUND: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer has been emphasized, however, there is no general agreement as to how immunohistochemical assays should be evaluated. It is critical to evaluate hormone receptor status when considering response to endocrine therapy. METHODS: Estrogen receptor (ER) and progesterone receptor (PgR) expression was examined by immunohistochemistry using Allred's score for primary breast tumors from 75 metastatic breast cancer patients who received first-line treatment with endocrine therapy (56 patients received tamoxifen, 11 patients received aromatase inhibitors, and 8 patients received LH-RH agonist or other endocrine reagents) on relapse. Correlation between hormone receptor status and response to endocrine therapy as well as post-relapse survival was analyzed. RESULTS: The most significant correlation between positive ER expression and response to any endocrine therapy (p = 0.011) or tamoxifen only (p = 0.030) occurred when the cutoff score was set at 10%. When the evaluation was based on Allred's score (TS), a cutoff point of TS>or=4 showed a more significant association between positive ER expression and response to all kinds of endocrine therapy (p = 0.020) or tamoxifen only (p = 0.047). When evaluated at a cutoff point of 1% positive cells, there were fifteen patients with both ER- and PgR-negative tumors, and three patients (20.0%) responded to the therapy. Patients with 1% or more ER or PgR positive cells had better survival after relapse (p = 0.0005 and p = 0.0008, respectively). CONCLUSIONS: The proportion score alone might be enough to predict hormone responsiveness and post-relapse survival in metastatic breast cancer. The cutoff might be set low, for example 1%, especially for metastatic disease.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Tamoxifen/therapeutic use , Breast Neoplasms/secondary , Chemotherapy, Adjuvant , Female , Hormone Replacement Therapy , Humans , Immunoenzyme Techniques , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Prognosis , Survival Rate
17.
Cancer Lett ; 237(1): 123-9, 2006 Jun 08.
Article in English | MEDLINE | ID: mdl-16019133

ABSTRACT

The transcriptional function of estrogen receptor alpha (ERalpha) can be modulated by co-regulatory proteins. In the present study, therefore, the level of expression of one of the co-regulator Nuclear Receptor Co-repressor 1 (NCOR1) mRNA has been assessed by quantitative real-time RT-PCR in 160 cases of invasive breast carcinoma. It was found that NCOR1 mRNA was expressed at significantly higher levels in patients over 50 years of age, without axillary lymph node involvement, with tumor size less than 2 cm, with low or intermediate histological grade, with ERalpha/PgR-positive and with HER2 negative tumors. Patients with high levels of expression of NCOR1 mRNA have a better prognosis than those with low expression. Univariate and multivariate prognostic analysis demonstrated that NCOR1 mRNA is an independent prognostic factor for breast cancer.


Subject(s)
Breast Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Nuclear Proteins/metabolism , Repressor Proteins/metabolism , Adult , Age Factors , Aged , Aged, 80 and over , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Estrogen Receptor alpha/metabolism , Female , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Invasiveness , Nuclear Proteins/analysis , Nuclear Proteins/genetics , Nuclear Receptor Co-Repressor 1 , Prognosis , RNA, Messenger/metabolism , Receptor, ErbB-2/metabolism , Receptors, Progesterone/metabolism , Repressor Proteins/analysis , Repressor Proteins/genetics , Survival Analysis
18.
Breast Cancer Res ; 7(5): R753-64, 2005.
Article in English | MEDLINE | ID: mdl-16168121

ABSTRACT

INTRODUCTION: Endocrine therapy is the most important treatment option for women with hormone-receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and crosstalk between ER and other growth factor signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified. METHODS: Using immunohistochemical techniques, we focused on the expression and phosphorylation of hormone receptors themselves and examined the phosphorylation of ER-alpha Ser118 and ER-alpha Ser167 and the expression of ER-alpha, ER-beta1, ER-betacx/beta2, progesterone receptor (PR), PRA, and PRB in the primary breast carcinomas of 75 patients with metastatic breast cancer who received first-line treatment with endocrine therapy after relapse. RESULTS: Phosphorylation of ER-alpha Ser118, but not Ser167, was positively associated with overexpression of HER2, and HER2-positive tumors showed resistance to endocrine therapy. The present study has shown for the first time that phosphorylation of ER-alpha Ser167, but not Ser118, and expression of PRA and PRB, as well as ER-alpha and PR in primary breast tumors are predictive of response to endocrine therapy, whereas expression of ER-beta1 and ER-betacx/beta2 did not affect response to the therapy. In addition, patients with either high phosphorylation of ER-alpha Ser167, or high expression of ER-alpha, PR, PRA, or PRB had a significantly longer survival after relapse. CONCLUSION: These data suggest that phosphorylation of ER-alpha Ser167 is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in metastatic breast cancer.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/pathology , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Phosphoserine/metabolism , Amino Acid Sequence , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , COS Cells , Chlorocebus aethiops , Epidermal Growth Factor/pharmacology , Estradiol/pharmacology , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Metastasis , Phosphorylation , Prognosis , Receptor, ErbB-2/genetics , Receptors, Progesterone/genetics , Receptors, Progesterone/metabolism , Recombinant Proteins/pharmacology , Recurrence , Survival Analysis , Transfection
19.
Breast Cancer Res Treat ; 94(1): 11-6, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16172792

ABSTRACT

Estrogen is well-established as a mitogenic factor implicated in the tumorigenesis and progression of breast cancer via its binding to the estrogen receptor alpha (ERalpha). Recent data indicate that chromatin inactivation mediated by histone deacetylation (HDAC) and DNA methylation is a critical component of ERalpha silencing in human breast cancer cells. The aim of this study was to determine the expression of the HDAC1 gene in malignant human breast tissue and to correlate our observations with available clinical information. In the present study, the level of expression of HDAC1 mRNA was assessed by LightCycler-based quantitative real-time reverse transcriptase (RT)-PCR analysis in 162 cases of invasive carcinoma of the breast. Associations between HDAC1 mRNA expression and different clinicopathological factors were sought. It was found that HDAC1 mRNA was expressed at significantly higher levels in tumors from patients over 50 years of age and in those tumors without axillary lymph node involvement, that are less than 2 cm, that are of a non-high histological grade, that are HER2 negative and that are ERalpha/PgR positive. Patients with tumors displaying high levels of HDAC1 mRNA expression tended to have a better prognosis in terms of both disease-free and overall survival. However, univariate and multivariate analysis did not show HDAC1 mRNA expression level to be an independent prognostic factor for either disease-free or overall survival. These results imply that HDAC1 mRNA expression could have potential as an endocrine response marker and may have prognostic implications for breast cancer progression.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Histone Deacetylases/metabolism , RNA, Neoplasm/metabolism , Age Distribution , Biomarkers, Tumor/genetics , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Disease-Free Survival , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Female , Gene Silencing , Histone Deacetylase 1 , Histone Deacetylases/genetics , Humans , Japan/epidemiology , Linear Models , Middle Aged , Multivariate Analysis , Prognosis , RNA, Messenger/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptors, Progesterone/genetics , Receptors, Progesterone/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate
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