RESUMEN
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.
Asunto(s)
Luz , Oryza/metabolismo , Fotosíntesis , Hojas de la Planta/metabolismo , Oryza/crecimiento & desarrollo , Oryza/efectos de la radiación , Hojas de la Planta/efectos de la radiaciónRESUMEN
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.
Asunto(s)
Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Antígeno Ki-67/metabolismo , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Receptores de Estrógenos/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores Farmacológicos/metabolismo , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Terapia de Reemplazo de Hormonas , Humanos , Antígeno Ki-67/genética , Persona de Mediana Edad , Estadificación de Neoplasias , Posmenopausia , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/análisis , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismoRESUMEN
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.
Asunto(s)
Androstadienos/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Histona Acetiltransferasas/análisis , Receptores de Estrógenos/análisis , Transactivadores/análisis , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Receptor alfa de Estrógeno/análisis , Receptor beta de Estrógeno/análisis , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Coactivador 3 de Receptor Nuclear , Fosforilación , Receptores de Progesterona/análisisRESUMEN
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.
Asunto(s)
Variación Genética/genética , Glycine max/genética , Algoritmos , Alelos , Cruzamiento/métodos , Aprendizaje Profundo , Genotipo , Ensayos Analíticos de Alto Rendimiento/métodos , Fotosíntesis/genética , Hojas de la Planta/genética , Estomas de Plantas/genéticaRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/mortalidad , Receptor alfa de Estrógeno/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Serina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/metabolismo , Receptor alfa de Estrógeno/química , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Fosforilación , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptor beta de Estrógeno/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Pronóstico , Isoformas de Proteínas , ARN Mensajero , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de SupervivenciaRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/mortalidad , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Neoplasias de la Mama/genética , Supervivencia sin Enfermedad , Femenino , Expresión Génica , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , ARN Mensajero/análisis , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisisRESUMEN
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.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/fisiopatología , Carcinoma Ductal de Mama/fisiopatología , Resistencia a Antineoplásicos , Proteína p53 Supresora de Tumor/biosíntesis , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/secundario , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Carcinoma Ductal de Mama/terapia , Femenino , Genes erbB-2/fisiología , Humanos , Antígeno Ki-67/biosíntesis , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Análisis de SupervivenciaRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas Nucleares/análisis , Proteínas Nucleares/genética , Co-Represor 1 de Receptor Nuclear , Pronóstico , ARN Mensajero/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Proteínas Represoras/análisis , Proteínas Represoras/genética , Análisis de SupervivenciaRESUMEN
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.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/uso terapéutico , Neoplasias de la Mama/secundario , Quimioterapia Adyuvante , Femenino , Terapia de Reemplazo de Hormonas , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Floxuridina/administración & dosificación , Administración Oral , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/patología , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Fosfoserina/metabolismo , Secuencia de Aminoácidos , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Células COS , Chlorocebus aethiops , Factor de Crecimiento Epidérmico/farmacología , Estradiol/farmacología , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis de la Neoplasia , Fosforilación , Pronóstico , Receptor ErbB-2/genética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Proteínas Recombinantes/farmacología , Recurrencia , Análisis de Supervivencia , TransfecciónRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/metabolismo , Adulto , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Proteínas tau/metabolismoRESUMEN
INTRODUCTION: Many laboratories are currently evaluating the usefulness of determination of HER2, p53, and Ki67 proliferation indices using immunohistochemical techniques in cancer. Although the available studies suggest that these factors might indeed be helpful in making treatment decisions in cancer patients, their clinical usefulness is still controversial. METHODS: Expression of HER2, p53, and Ki67 was examined by immunohistochemistry in samples of breast tissue from 506 patients with invasive ductal carcinoma, obtained between 1981 and 1999 (median follow up period 82 months), and their significance for prognosis was analyzed. RESULTS: Of the 506 carcinoma tissue samples, 20.1%, 29.0%, and 53.6% were positive for HER2 over-expression, p53 protein accumulation, and Ki67 expression, respectively. Over-expression of HER2 significantly reduced disease free (P = 0.02) and overall survival (P = 0.005). Accumulation of p53 protein significantly decreased disease free (P = 0.01) and overall survival (P = 0.01). Patients with tumors that were positive for both HER2 and p53 relapsed and died within a significantly shorter period of time after surgery (P = 0.0001 and P < 0.0001, respectively). In multivariate analysis, patients with both HER2 and p53 positive tumors had considerably decreased overall survival (P = 0.04), as did patients with larger tumor size and positive lymph node status. CONCLUSION: The findings of the present study indicate that the coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancer.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Receptor ErbB-2/biosíntesis , Proteína p53 Supresora de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
BACKGROUND: Estrogen is a mitogenic factor that is implicated in the genesis and progression of breast cancer via its binding to estrogen receptor (ER)-alpha. Synthesis of estrogen in situ is believed to be catalyzed mainly by aromatase. Previous studies comparing the relative contributions from tumor cells and stromal cells to local estrogen synthesis, as assessed by immunohistochemical analysis, were quite controversial and no consistent relationship was found between the presence of aromatase and any clinicopathologic factor. In addition, previous studies into aromatase gene expression and clinicopathologic factors are limited. METHODS: We assessed the level of expression of aromatase mRNA, using quantitative real-time RT-PCR, in 162 cases of invasive ductal carcinoma of the breast. Associations between aromatase expression and different clinicopathologic factors were sought. RESULTS: It was found that aromatase mRNA was expressed at significantly higher levels in patients older than 50 years, in those without axillary lymph node involvement, in those with tumor size less than 2 cm, and in ER-alpha positive tumors. However, no relationship was found between aromatase mRNA expression and any other clinicopathologic factor, including histologic grade and progesterone receptor status. Patients with high levels of expression of aromatase mRNA tended to have a better prognosis than did those patients with low expression. CONCLUSION: These findings imply that ER-alpha and aromatase may be coexpressed in endocrine responsive patients. They may also indicate that aromatase expression could be a marker of endocrine responsiveness, and it may have prognostic implications for breast cancer progression.
Asunto(s)
Aromatasa/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , ARN Mensajero/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Supervivencia sin Enfermedad , Receptor alfa de Estrógeno , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Metástasis Linfática , Persona de Mediana Edad , Pronóstico , ARN Mensajero/genética , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
The assessment of the estrogen receptor (ER) alpha and the progesterone receptor (PgR) in breast cancer tissues is important for discriminating between hormone-dependent and hormone-independent tumors. ERbeta, a more recently discovered ER, may influence estrogen action through the ERalpha pathway. To evaluate the clinical significance of these receptors in the response to endocrine therapy, we investigated their expression in primary breast cancer tissues. ERalpha and PgR were evaluated using immunohistochemistry (IHC) and enzyme immunoassay (EIA) and ERbeta expression was determined using IHC and reverse transcription-polymerase chain reaction. When the cut-off level of EIA was set at 13 fmol/mg protein for ERalpha and that for IHC was set as an IHC score between 2 and 3, a significant correlation between ERalpha EIA and IHC was seen (concordance rate 88.4%). This indicates that this cut-off level of ERalpha IHC can be adopted to quantify breast cancer prognoses. Furthermore, the tumors with positive expression of ERalpha IHC or PgR IHC using this criterion were significantly related to the response to endocrine therapy. Additionally, tumors with positive expression of ERbeta wild-type tended to have a better response to endocrine therapy than negative ones, and tamoxifen responders tended to exhibit a lower ratio of ERbetacx (one of the ERbeta variants) to ERbeta wild-type than nonresponders. The results concerning ERbeta are not yet fully understood; further investigations and evaluations should analyze the role of ERbeta wild-type and variant type in breast cancer treatment.
Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias de la Mama/metabolismo , Receptores de Estrógenos/biosíntesis , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Humanos , Reacción en Cadena de la Polimerasa , ARN Neoplásico/análisisRESUMEN
BACKGROUND: The marked improvement in breast cancer mortality in the United Kingdom (UK) has attracted worldwide interest. To understand the details of this phenomenon the morbidity and mortality rates of breast cancer in the UK during the past 30 years were analyzed. METHODS: The official publications and statistical data were available and downloaded at the official UK Web sites of the National Health Service, National Statistics and Cancer Research Organization. Parts of the data were obtained directly from the National Cancer Intelligence Centre of UK. RESULTS: After the beginning of breast screening the morbidity of the subject age group soared up to the level of an age group that was 10 years older. Noninvasive carcinoma was often discovered in the subject age group after the beginning of breast screening and constituted 8.3%of all cases. The mortality rates, however, began to decrease before the start of screening and fell clearly even in age groups other than that of the study group and particularly in elderly women. CONCLUSIONS: Not only the prevalence of breast screening but also the increase of early stage cancer in all age groups have probably resulted from improvements in diagnostic technology and heightened social interest and awareness. In addition, the development of adjuvant endocrine therapy must have influenced the evident improvement in mortality of breast cancer in the UK.
Asunto(s)
Neoplasias de la Mama/mortalidad , Tamizaje Masivo/estadística & datos numéricos , Adulto , Factores de Edad , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Femenino , Humanos , Persona de Mediana Edad , Morbilidad , Mortalidad/tendencias , Programas Nacionales de Salud , Estadificación de Neoplasias , Educación del Paciente como Asunto , Estudios Retrospectivos , Condiciones Sociales , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: An estrogen receptor (ER) alpha variant with an A-to-G transition at nucleotide 908 (A908G) has been identified in typical hyperplastic mammary epithelium. This somatic mutation, which induces a Lys-to-Arg substitution at residue 303 within exon 4 at the border of the hinge and hormone-binding domains of the ER alpha, shows increased sensitivity to estrogen compared with wild-type ER alpha. METHODS: To investigate whether this mutation was present in breast lesions, we performed mutation analyses using the PCR-restriction fragment length polymorphism (RFLP) method in 7 cases of hyperplasia, 18 cases of benign breast tumor, 26 cases of ductal carcinoma in situ (DCIS) and 215 cases of invasive ductal carcinoma (IDC). When we extracted DNA, the hyperplastic epithelium and cancer cells of DCIS were microdissected. We also performed direct sequencing analysis from 7 randomly-selected representative cases of hyperplasia, 9 cases of benign breast tumors, 11 cases of DCIS and 20 cases of IDC. RESULTS: No A908G mutation was found in the ER alpha gene in these breast lesions. CONCLUSION: This mutation might be absent or occur in so few cells as to be undetectable by PCR-RFLP or direct sequencing.
Asunto(s)
Pueblo Asiatico/genética , Enfermedades de la Mama/genética , Neoplasias de la Mama/genética , Mutación , Receptores de Estrógenos/genética , Adulto , Anciano , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Femenino , Humanos , Japón , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Lesiones Precancerosas/genética , Análisis de Secuencia de ADNRESUMEN
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.