RESUMEN
Progesterone receptor membrane component 1 (PGRMC1) is mediating strong breast cancer cell proliferation induced by certain synthetic progestogens which we have shown within already published in vitro studies. Aim was now to use an animal model, to compare tumor growth using progesterone and its isomer dydrogesterone with norethisterone, which elicited in our in vitro studies the strongest proliferating effect. For the first time, we wanted to investigate if growth can be correlated both with blood concentrations and tissue expression of PGRMC1 to identify if PGRMC1 could be a new tumor marker. Prospective, randomized, blinded, placebo-controlled four-arm study (45-50 days); PGRMC1-transfected or empty-vector T47D- and MCF7-xenotransplants were each treated with estradiol (E2) +placebo; E2 + progesterone; E2 + norethisterone; E2 + dydrogesterone; blood PGRMC1 assessed by a novel ELISA, tissue expression by immunohistochemistry. PGRMC1-transfected tumors further increased with E2 + norethisterone but not with E2-dydrogesterone or E2-progesterone. In both PGRMC1-xenograft groups (T47D, MCF7) with E2/norethisterone, the blood concentrations and tissue expression of PGRMC1 were higher than in all other 14 groups (p < .05), with positive significant correlation between blood PGRMCI concentrations and tissue PGRMC1 expression. In the presence of PGRMC1, certain progestogens could increase the growth of breast tumor, which now also should be tested in clinical studies.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Didrogesterona/farmacología , Neoplasias Mamarias Experimentales/patología , Proteínas de la Membrana/metabolismo , Noretindrona/farmacología , Progesterona/farmacología , Receptores de Progesterona/metabolismo , Animales , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Células MCF-7 , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/sangre , Neoplasias Mamarias Experimentales/metabolismo , Proteínas de la Membrana/sangre , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Placebos , Distribución Aleatoria , Receptores de Progesterona/sangreRESUMEN
TNBC represents the most malignant subtype of breast cancer with heterogenicity and poor prognosis. PGRMC1 has been reported to predict worse prognosis and correlate with MHT mediated signal transduction in breast cancer, whereas its involvement in TNBC remains poorly explored. The purpose of the study was to explore the roles of PGRMC1 in TNBC. Bioinformatic approaches were performed to analyzed the expression of PGRMC1 among different subtypes of breast cancers using RNA-seq data from the TCGA, METABRIC and GEO databases. PGRMC1 mRNA expression and survival in breast cancer were analyzed. Furthermore, we analyzed the expression of PGRMC1 in TNBC by single cell RNA-seq data and immunohistochemistry. The expression of PGRMC1 in TNBC group was significantly higher compared with that of Luminal subtypes, especially in the epithelia cells, which was further proved by IHC at protein level. Better overall survival (p = 0.027) was observed in the patients with lower expression of PGRMC1. Different states of hormone and Her2 receptors contributed to the distinct functions of PGRMC1. In TNBC, PGRMC1 might play an important role in mitochondrial functions. In summary, this study revealed the correlation between PGRMC1 expression and its clinical significance in TNBC, probably through mitochondria-associated pathway, which may provide new ideas for prognosis and therapy of TNBC.
RESUMEN
BACKGROUND: Research suggests that hormone replacement therapy may increase the risk of breast cancer, and progestins such as norethisterone (NET) play a key role in this phenomenon. We have demonstrated that microRNA-181a (miR-181a) suppresses NET-promoted breast cancer cell survival. Nonetheless, the effects of NET and miR-181a on the tumorigenesis of human breast epithelial cells have not yet been elaborated. METHODS: Assays of cell viability, proliferation, migration, apoptosis, and colony formation were performed to investigate the pro-tumorigenesis effect of NET and the effects of miR-181a on human breast epithelial MCF10A cells. The expressions of cell-proliferation-related genes and apoptotic factors were analyzed by quantitative RT-PCR and Western blot in MCF10A cells treated with NET and miR-181a. RESULTS: NET significantly increased MCF10A cell viability, proliferation, migration, and colony formation, but reduced cellular apoptosis. In addition, NET increased the expression of progesterone receptor membrane component 1 (PGRMC1), EGFR, B-cell lymphoma 2, cyclin D1, and proliferating cell nuclear antigen, but decreased the expression of pro-apoptosis factors, such as Bax, caspase-7, and caspase-9. Overexpression of miR-181a strongly inhibited the effects of NET on MCF10A cells and abrogated NET-stimulated PGRMC1, EGFR, and mTOR expression. CONCLUSIONS: Activation of the PGRMC1/EGFR-PI3K/Akt/mTOR signaling pathway is the primary mechanism underlying the pro-tumorigenesis effects of NET on human breast epithelial MCF10A cells. Additionally, miR-181a can suppress the effects of NET on these cells. These data suggest a therapeutic potential for miR-181a in reducing or preventing the risk of breast cancer in hormone replacement therapy using NET.
RESUMEN
OBJECTIVES: Progesterone receptor membrane component-1 (PGRMC1) in breast cancer tissue has been suggested to predict a worse prognosis. The aim of this study was to assess for the first time whether PGRMC1 expressed in cancer tissue is associated with PGRMC1 blood concentrations and whether both are correlated with clinical tumour characteristics known to predict a worse outcome. METHODS: In total, 201 patients with invasive breast cancer and 65 with benign breast disease (control group) were recruited. PGRMC1 blood concentrations were measured by a recently developed ELISA, PGRMC1 in breast cancer tissue was assessed by immunohistochemistry, and the correlation between the two was calculated. Receiver-operating characteristic (ROC) curve analysis was used to assess area under the curve (AUC). Furthermore, PGRMC1 was correlated with tumour characteristics such as tumour diameter, tumour grade and metastatic status, and with known blood tumour markers. RESULTS: AUC for the breast cancer group was 0.713, which was significantly higher than in the control group (p < 0.01). Blood PGRMC1 concentrations had a strong (positive) correlation with tissue PGRMC1 expression (p < 0.01) but were not associated with serum tumour markers CEA, CA125, CA153 and TPS. Tissue PGRMC1, ER and cancer stage were positively associated with blood PGRMC1 (p < 0.05). CONCLUSIONS: As PGRMC1 expression levels in cancer tissue were significantly correlated with PGRMC1 in blood, and because concentrations in blood were also positively associated with breast tumour characteristics known to predict a worse prognosis, PGRMC1 may be valuable as a new tumour marker and may be superior to known tumour markers such as CEA, CA125, CA153 and TPS.
Asunto(s)
Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama , Proteínas de la Membrana/sangre , Proteínas de la Membrana/metabolismo , Receptores de Progesterona/sangre , Receptores de Progesterona/metabolismo , Adulto , Anciano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Adulto JovenRESUMEN
OBJECTIVES: Progesterone receptor membrane component-1 (PGRMC1) expressed in breast cancer tissue has been suggested to predict a worse prognosis. The aim of this study was to assess for the first time if blood concentrations of PGRMC1 are also associated with receptor status, tumor diameter, grading, and lymphatic status. The second aim was comparison with known tumor markers. METHODS: A total of 372 women, including 278 patients with invasive breast cancer, 65 with benign breast disease, and 29 healthy women (control), were recruited. PGRMC1 blood concentrations were measured by a recently developed enzyme-linked immunosorbant assay, and were correlated to predictive tumor characteristics and compared with serum carcinoembryonic antigen (CEA), CA125, and CA153. RESULTS: PGRMC1 levels in the cancer group were significantly higher than in the control and benign group and increased with higher cancer stages (Pâ<â0.05). PGRMC1 concentrations in the estrogen receptor (ER)+/progesterone receptor (PR)+ group were higher than in the ER-/PR- group, related to larger tumor diameter and the presence of lymph node metastasis (Pâ<â0.05). Multivariable linear regression analysis was used to control the confounding factors. Tumor diameter, lymphatic metastasis, and ER (but not PR) were positively associated with PGRMC1 (Pâ<â0.05). The receiver-operating characteristic curve (ROC) analysis was used to assess area under the curve (AUC). AUC was 87.9% for stages III+IV and 80.8% for stages I+II (Pâ<â0.01). ROC did not find significant effects on AUC for CA125, only significant for CEA and CA153 for stages III+IV. CONCLUSION: As PGRMC1 levels are positively associated with breast tumor characteristics known to predict a worse diagnosis, PGRMC1 may be valuable as a new tumor marker, and superior to CEA, C125, and CA153. Because of the positive association with ER-expression, PGRMC1 may interact with this receptor.
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Antígenos de Neoplasias/sangre , Neoplasias de la Mama/sangre , Antígeno Ca-125/sangre , Proteínas de la Membrana/sangre , Receptores de Superficie Celular/sangre , Receptores de Progesterona/sangre , Adulto , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Adulto JovenRESUMEN
OBJECTIVES: A few observational studies have suggested that progesterone and dydrogesterone may have a lower risk of breast cancer than other progestogens. In our earlier xenograft animal experiments, progesterone did not stimulate breast tumors. The aim of this study was to test dydrogesterone for the first time. The study also evaluated the effects of PGRMC1 on proliferation with progestogens. METHODS (1): In-vitro study. The proliferative effects of dydrogesterone and of progesterone were assessed in vitro using T47D cells transfected with PGRMC1 or empty vector in the presence or absence of estradiol. Additionally, to find the strongest proliferator for inclusion as a comparator in the xenograft animal study, norethisterone, levonorgestrel, desogestrel, dienogest, drospirenone, nomegestrol, and cyproterone acetate were tested. METHODS (2): Xenograft main study. PGRMC1-transfected or empty-vector T47D and MCF7 xenotransplants were each treated with four different hormonal preparations: E2+placebo; E2+dydrogesterone; E2+progesterone; E2+norethisterone. A total of 112 castrated mice were randomly allocated to the 16 groups. This was thus a prospective, randomized, blinded, placebo-controlled four-arm study (45-50 days) with the two T47D and two MCF7 xenografts. Tumor volumes were monitored twice weekly. RESULTS (1): In-vitro study. The strongest proliferation was with norethisterone, but only with PGRMC1-transfected cells. There was significant proliferation with dydrogesterone, but not with progesterone in the absence of estradiol. However, no increase in proliferation was achieved by adding dydrogesterone to estradiol compared with the proliferation induced with estradiol alone, in contrast to norethisterone. RESULTS (2): Xenograft main study. There was significantly faster tumor growth with norethisterone + E2 than with E2+placebo in T47D and MCF7 PGRMC1 xenografts, but not with dydrogesterone + E2 or progesterone + E2. There was less tumor growth in empty-vector xenografts, without between-group differences. CONCLUSION: PGRMC1 increases the breast-cell proliferation effects of certain progestogens, including dydrogesterone, in contrast to progesterone, but not during estradiol-induced proliferation, either in vitro or in a xenograft animal model, in contrast to norethisterone. Thus the proliferative potency of dydrogesterone may be similar to that of progesterone. Clinical studies in women overexpressing PGRMC1 are recommended.
Asunto(s)
Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Progestinas/farmacología , Receptores de Progesterona/metabolismo , Androstenos/farmacología , Animales , Acetato de Ciproterona/farmacología , Didrogesterona/farmacología , Estradiol/farmacología , Femenino , Xenoinjertos , Humanos , Técnicas In Vitro , Células MCF-7 , Megestrol/análogos & derivados , Megestrol/farmacología , Ratones , Ratones Desnudos , Nandrolona/análogos & derivados , Nandrolona/farmacología , Noretindrona/farmacología , Progesterona/farmacología , Estudios ProspectivosRESUMEN
OBJECTIVE: To evaluate the prevalence of adverse pregnancy outcomes in healthy Chinese women and to investigate whether these outcomes could be decreased in patients with polycystic ovary syndrome (PCOS) by ethinylestradiol/cyproterone acetate (EE/CPA) pretreatment. DESIGN: Retrospective study. SETTING: Medical university. PATIENT(S): Six thousand healthy women (group A) were selected from 24,566 pregnant women by randomized sampling. Four hundred forty-eight patients with PCOS without EE/CPA pretreatment were assigned to group B, and 222 patients with PCOS with 3 months of pretreatment to group C. All patients with PCOS had biochemical and/or clinical hyperandrogenism and conceived within 3 monthly ovulation inductions using clomiphene. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), premature delivery (PD), and neonatal birth weight. RESULT(S): The prevalence of GDM, PIH, and PD was higher in group B than in groups A and C (A vs. B vs. C: GDM, 21.2% vs. 35.0% vs. 22.5%; PIH, 6.5% vs. 14.1% vs. 7.7%; PD, 5.4% vs. 8.6% vs. 6.8%). No significant difference was found in neonatal birth weight. After adjusting for age, pregestational body mass index, education level, and employment status, PCOS without pretreatment increased the risk of GDM (adjusted odds ratio [aOR] = 1.666; 95% confidence interval [CI], 1.340-2.072), PIH (aOR = 1.487; 95% CI, 1.093-2.023), and PD (aOR = 1.522; 95% CI 1.051-2.205), compared with healthy women. No increased risk was found in group C. CONCLUSION(S): In our highly selected study population, patients with PCOS are more likely to develop GDM, PIH, and PD. Pretreatment with EE/CPA was associated with a lower risk of GDM, PIH, and PD.
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Antagonistas de Andrógenos/efectos adversos , Clomifeno/administración & dosificación , Acetato de Ciproterona/efectos adversos , Etinilestradiol/efectos adversos , Fármacos para la Fertilidad Femenina/administración & dosificación , Infertilidad Femenina/terapia , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Complicaciones del Embarazo/inducido químicamente , Adulto , Antagonistas de Andrógenos/administración & dosificación , Peso al Nacer , China/epidemiología , Clomifeno/efectos adversos , Acetato de Ciproterona/administración & dosificación , Diabetes Gestacional/inducido químicamente , Diabetes Gestacional/epidemiología , Combinación de Medicamentos , Etinilestradiol/administración & dosificación , Femenino , Fármacos para la Fertilidad Femenina/efectos adversos , Humanos , Hipertensión Inducida en el Embarazo/inducido químicamente , Hipertensión Inducida en el Embarazo/epidemiología , Recién Nacido , Infertilidad Femenina/diagnóstico , Infertilidad Femenina/epidemiología , Infertilidad Femenina/fisiopatología , Inducción de la Ovulación/efectos adversos , Síndrome del Ovario Poliquístico/diagnóstico , Síndrome del Ovario Poliquístico/epidemiología , Síndrome del Ovario Poliquístico/fisiopatología , Embarazo , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/epidemiología , Nacimiento Prematuro/inducido químicamente , Nacimiento Prematuro/epidemiología , Prevalencia , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Tiempo para Quedar Embarazada , Resultado del Tratamiento , Adulto JovenRESUMEN
Nesfatin-1 is an anorexigenic peptide involved in energy homeostasis. Recently, nesfatin-1 was reported to decrease blood glucose level and improve insulin sensitivity in high-fat diet-fed rats. However, little information is known about the influence of nesfatin-1 on lipid metabolism either in physiological or diabetic condition. This study undertook whether nesfatin-1 was involved in the pathophysiology in Streptozotocin-induced type 2 diabetic mice (T2DM), which was induced by a combination of high-calorie diet and two low-doses Streptozotocin. We observed that plasma nesfatin-1 was significantly increased while expression of nesfatin-1 neurons were decreased in hypothalamus in diabetes group compared to only high-calorie diet control group; intravenous injection of nesfatin-1 decreased 0-1h, 0-2h, 0-3h cumulative food intake in T2DM, but 0-24h total food intake had no difference between groups. Body weight and plasma FFA were normalized after nesfatin-1(10 µg/Kg) administration for 6 days. These results suggested that nesfatin-1 improved lipid disorder in T2DM. It was found that blood glucose and insulin resistance coefficient decreased with treatment of nesfatin-1 (both in 1 µg/Kg and 10 µg/Kg doses) in diabetes mice. For further understanding the role of nesfatin-1 on lipid metabolism, we detected p-AMPK and p-ACC of skeletal muscle in T2DM using western blotting. The expression of p-AMPK and p-ACC increased when nesfatin-1 was given with doses 1 µg/Kg but not in doses 10 µg/Kg. Taken together, nesfatin-1 participated in the development of T2DM and stimulated free fatty acid utilization via AMPK-ACC pathway in skeletal muscle in T2DM.