RESUMEN
BACKGROUND: In various cancers, overexpression of cyclooxygenase (COX)-2 and elevated prostaglandin (PG) E2 synthesis have been associated with tumor development and progression. The potential of COX-2 inhibitors in cancer prevention and treatment has been shown repeatedly; however, their clinical use is limited due to toxicity. PGE2 signals via EP receptors 1-4, whose functions are analyzed in current research in search for targeted anti-PG therapies. EP2 and EP4 rather promote tumorigenesis, while the role of EP3, especially in breast cancer, is not yet clear and both pro- and anti-tumorigenic effects have been described. Our study evaluates EP3 receptor expression in sporadic breast cancer and its association with clinicopathological parameters, progression-free and overall survival. METHODS: Two hundred eighty-nine sporadic breast cancer samples without primary distant metastasis were immunohistochemically analyzed for EP3 receptor expression. Tissue was stained with primary anti-EP3-antibodies. Immunoreactivity was quantified by the immunoreactivity-score (IRS); samples with an IRS ≥ 2 scored as EP3 positive. Chi-squared and Mann-Whitney-U test were used for comparison of data; Kaplan-Meier estimates and Cox-regression were used for survival analyses. RESULTS: EP3 receptor was expressed in 205 of 289 samples analyzed (70.9%). EP3 receptor expression was not associated with clinicopathological parameters (e. g. tumor size, hormone receptors, lymph node status). Kaplan-Meier estimates showed a significant association of EP3 positivity with improved progression-free survival (p = 0.002) and improved overall survival (p = 0.001) after up to 10 years. Cox regression analysis confirmed EP3 positivity as a significant prognostic factor even when other known prognosticators were accounted for. CONCLUSIONS: In sporadic breast cancer, EP3 receptor expression is not significantly associated with clinicopathological parameters but is a significant prognostic factor for improved progression-free and overall survival. However, the functional aspects of EP3 receptor in breast cancer and the way how EP3 may oppose the pro-tumorigenic effects of PGE2 elevation and COX-2 overexpression are not fully understood so far. Further studies aiming at identification of the factors regulated by EP3 are necessary to evaluate the possibility of targeting EP3 in future anti-tumor therapy in breast cancer.
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Neoplasias de la Mama/genética , Carcinogénesis/genética , Pronóstico , Subtipo EP3 de Receptores de Prostaglandina E/genética , Anciano , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Dinoprostona/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Estimación de Kaplan-Meier , Persona de Mediana EdadRESUMEN
PURPOSE: We aimed to determine whether embryo culture induces markers of cellular senescence and whether these effects were dependent on culture conditions. METHODS: Murine blastocysts were derived in vitro and in vivo and assessed for 2 primary markers of senescence: senescence-associated ß-galactosidase (SA-ß-gal) and phosphorylated H2A.X (γ-H2A.X), the latter being a mark of DNA oxidative damage. Expression of senescence-associated genes p21, p16, and interleukin 6 (IL6) were also assessed. RESULTS: Compared with in vivo-derived blastocysts, in vitro embryos had high levels of SA-ß-gal, nuclear γ-H2A.X, and p21 mRNA expression, indicating that a senescence-like phenotype is induced by in vitro culture. To determine the role of culture conditions, we studied the effect of oxygen (5 % vs 20 %) and protein supplementation on senescence markers. Blastocysts in reduced oxygen (5 %) had low levels of both SA-ß-gal and γ-H2A.X compared with blastocysts cultured in ambient oxygen. Senescence markers also were reduced in the presence of protein, suggesting that antioxidant properties of protein reduce oxidative DNA damage in vitro. CONCLUSION: Elevated SA-ß-gal, γ-H2A.X, and p21 suggest that in vitro stress can induce a senescence-like phenotype. Reduced oxygen during embryo culture minimizes these effects, providing further evidence for potential adverse effects of culturing embryos at ambient oxygen concentrations.
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Biomarcadores/metabolismo , Blastocisto/metabolismo , Senescencia Celular/fisiología , Oxígeno/metabolismo , Animales , Antioxidantes/metabolismo , Células Cultivadas , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Daño del ADN/fisiología , Histonas/metabolismo , Técnicas In Vitro/métodos , Interleucina-6/inmunología , Ratones , ARN Mensajero , Especies Reactivas de Oxígeno/metabolismo , beta-Galactosidasa/metabolismo , Quinasas p21 Activadas/metabolismoRESUMEN
BACKGROUND: Despite the excellent prognosis of Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome. METHODS: We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens. The Kaplan-Meier method and Cox proportional hazard model were applied for survival and multivariable analyses. A machine-learning approach was used to validate variables for predicting recurrence and death. RESULTS: Of 1021 included cancers, 17.7% were rated L1CAM-positive. Of these L1CAM-positive cancers, 51.4% recurred during follow-up compared with 2.9% L1CAM-negative cancers. Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Log-rank P < .001). Multivariable analyses revealed an increase in the likelihood of recurrence (hazard ratio [HR] = 16.33; 95% confidence interval [CI] = 10.55 to 25.28) and death (HR = 15.01; 95% CI = 9.28 to 24.26). In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree (CRT)identified L1CAM as the best variable for predicting recurrence (sensitivity = 0.74; specificity = 0.91) and death (sensitivity = 0.77; specificity = 0.89). CONCLUSIONS: To our knowledge, L1CAM has been shown to be the best-ever published prognostic factor in FIGO stage I, type I endometrial cancers and shows clear superiority over the standardly used multifactor risk score. L1CAM expression in type I cancers indicates the need for adjuvant treatment. This adhesion molecule might serve as a treatment target for the fully humanized anti-L1CAM antibody currently under development for clinical use.
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Biomarcadores de Tumor/análisis , Neoplasias Endometriales/química , Neoplasias Endometriales/diagnóstico , Recurrencia Local de Neoplasia/química , Recurrencia Local de Neoplasia/diagnóstico , Molécula L1 de Adhesión de Célula Nerviosa/análisis , Adulto , Anciano , Braquiterapia , Supervivencia sin Enfermedad , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Humanos , Histerectomía , Inmunohistoquímica , Estimación de Kaplan-Meier , Escisión del Ganglio Linfático , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Ovariectomía , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante , Estudios Retrospectivos , Medición de Riesgo , Salpingectomía , Sensibilidad y EspecificidadRESUMEN
Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer.
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Histonas/metabolismo , Indoles/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Poli(ADP-Ribosa) Polimerasas/metabolismo , Apoptosis/efectos de los fármacos , Proteína BRCA2/genética , Línea Celular Tumoral , Fragmentación del ADN/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Histonas/genética , Humanos , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Topotecan/administración & dosificación , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
BACKGROUND: The objective of this case-control study was to identify any association of metformin intake with the survival of patients with ovarian cancer. METHODS: In this retrospective case-control study, women with ovarian cancer who received metformin (cases) were compared with women with ovarian cancer who did not receive metformin (controls). A 2-layered analysis was conducted. In preliminary analysis, all cases (the OC cohort) were compared with controls at a 1:2 ratio. Subsequently, in definitive analysis, only patients who had epithelial ovarian cancer (the EOC cohort) were compared with controls at a 1:3 ratio. In the EOC cohort, cases were matched with controls for age (±5 years), International Federation of Gynecology and Obstetrics stage, and residual disease. Prognostic variables and disease specific survival were compared using chi-square tests, the Kaplan-Meier (log-rank) method, and Cox proportional hazards analysis. RESULTS: In a preliminary analysis of the OC cohort (72 cases and 143 controls), cases had better survival (5-year disease-specific survival for cases vs controls, 73% vs 44%; P = .0002). In the definitive analysis of the EOC cohort (61 cases and 178 controls), the distribution of age, disease stage, optimal cytoreduction, serous histology, and platinum chemotherapy remained similar between cases and controls (P > .05). Despite these similarities, cases had significantly better survival (5-year disease-specific survival for cases vs controls, 67% vs 47%; P = .007). On multivariate analysis, metformin remained an independent predictor of survival (hazard ratio, 2.2; 95% confidence interval, 1.2-3.8; P = .007) after controlling for disease stage, grade, histology, chemotherapy, body mass index, and surgical cytoreduction. CONCLUSIONS: The results of this study indicated an association of metformin intake with survival in patients with ovarian cancer. The receipt of metformin was associated with better survival, and the authors concluded that metformin is worthy of clinical trials in ovarian cancer.
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Metformina/uso terapéutico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Anciano , Antineoplásicos/administración & dosificación , Carcinoma Epitelial de Ovario , Estudios de Casos y Controles , Estudios de Cohortes , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/epidemiología , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/epidemiología , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Metformina/administración & dosificación , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/complicaciones , Neoplasias Glandulares y Epiteliales/epidemiología , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/epidemiología , Estudios Retrospectivos , Análisis de Supervivencia , Tasa de SupervivenciaRESUMEN
The pathogenesis of endometriosis is unclear, and several genetic, endocrine, immune, and environmental agents have been evaluated with no putative causative factors identified. Here, we show somatic genetic alterations involving HMGA1 (6p21) and HMGA2 (12q15) in 3 cases of polypoid endometriosis. The lesions involved the small bowel mesentery and perirectal soft tissue in 1 case and the posterior vaginal fornix and sigmoid colon serosa in 2 other cases, respectively. All had a polypoid configuration with cystically dilated irregular glands and fibrotic stroma, containing thick-walled vessels. Conventional cytogenetic analysis of 1 case showed 46,XX,t(5;12)(q13;q15) in all metaphases. Fluorescence in situ hybridization studies confirmed the balanced rearrangement of HMGA2. HMGA1 rearrangements were present in 2 additional cases. Rearrangements were exclusively found in the stromal component but not in the glandular component. These findings suggest that HMGA rearrangements likely contribute to the pathogenesis of endometriosis. However, additional studies are needed to better define the biologic role of this genetic alteration.