Background: The aim of this study is to provide an expression profile of ErbB/HER ligands in breast cancer. We analysed the relationships with their receptors, the bio-pathological features and ...prognosis. Patients and methods: Epidermal growth factor (EGF), transforming growth factor-α (TGFα), amphiregulin (AREG), betacellulin (BTC), heparin-binding EGF-like growth factor (HB-EGF), epiregulin (EREG) and neuregulins1–4 (NRG1–4) were quantified in 363 tumours by real-time reverse transcription–polymerase chain reaction using TaqMan probes. Results: Ligands were detected in 80%–96% of the cases, except NRG3 (42%) and EREG (45.5%). At least one ligand was expressed in 304 cases (cut-off: upper quartile). Almost all combinations of receptor and ligand co-expressions were observed, but TGFα is preferentially expressed in tumours co-expressing EGFR/HER3, NRG3 in those co-expressing EGFR/HER4, AREG and EREG in those co-expressing HER2/HER4. EGF and AREG were associated with estradiol receptors, small tumour size, low histoprognostic grading, high HER4 levels. TGFα, HB-EGF and NRG2 were negatively related to these parameters. In Cox univariate analyses, EGF was a prognostic factor. Conclusion: Our study demonstrates that (i) ErbB/HER ligands, including BTC and EREG, are expressed in most breast cancers; and (ii) TGFα, HB-EGF and NRG2 high expressions are related to the biological aggressiveness of the tumours.
Large earthquakes produce crustal deformation that can be quantified by geodetic measurements, allowing for the determination of the slip distribution on the fault. We used data from Global ...Positioning System (GPS) networks in Central Chile to infer the static deformation and the kinematics of the 2010 moment magnitude (M(w)) 8.8 Maule megathrust earthquake. From elastic modeling, we found a total rupture length of ~500 kilometers where slip (up to 15 meters) concentrated on two main asperities situated on both sides of the epicenter. We found that rupture reached shallow depths, probably extending up to the trench. Resolvable afterslip occurred in regions of low coseismic slip. The low-frequency hypocenter is relocated 40 kilometers southwest of initial estimates. Rupture propagated bilaterally at about 3.1 kilometers per second, with possible but not fully resolved velocity variations.
We reviewed the relationships between
ERBB2 amplification and/or overexpression in human breast cancer and the clinicopathological parameters described in the literature (97 studies involving 22
616 ...patients) in order to draw conclusions regarding its clinical interest. The mean of
ERBB2 positivity (26%, ranging from 5 to 55%) is not dependent on the method used to evaluate
ERBB2 amplification or overexpression. Despite the discrepancies observed between the different studies, several associations between
ERBB2 positivity and the classical clinicopathological parameters were noted. There are clear relationships between
ERBB2 positivity and the lack of steroid receptors, the histological subtypes of mammary tumours (ductal invasive and
in situ), worse histological and nuclear grades, aneuploidy and high rate of proliferation. In univariate analyses,
ERBB2 is strongly associated with poor prognosis. All these data indicate that
ERBB2 is a marker of aggressiveness of the tumour. However,
ERBB2 does not retain a clinical prognostic significance in multivariate analyses, since it is associated with several strong prognostic parameters. When considering the prognostic value of
ERBB2 in relation to treatment, a significantly worse survival of the treated patients is noted in
ERBB2 positive patients. This suggest that
ERBB2 could be a marker of reduced response to chemotherapy and hormonal treatment. With respect to the tumour response to treatment, the results, provided as yet by pilot studies, remain controversial and further investigations are necessary to evaluate the predictive value of
ERBB2. Finally, new therapeutic approaches targeting the cells overexpressing
ERBB2 have been developed.
We study a large Mw= 7.6 earthquake that occurred on 2007 November 14 in the Northern Chile seismic gap near the city of Tocopilla. Using a variety of seismic data we show that this earthquake ...ruptured only the lower part of the interplate seismic zone and generated a series of plate interface aftershocks. Two large aftershocks on 2007 November 15 ruptured the interplate zone oceanwards of the Mejillones Peninsula, a major geographical feature in the Antofagasta region. On 2007 December 16, a large Mw= 6.8 aftershock, that occurred near the southern bottom of the fault plane of the main event, is shown to be a slab-push earthquake located inside the subducted Nazca Plate and triggered by along slab compression. Aftershocks of this event demonstrate that it occurred on an almost vertical fault. The Tocopilla earthquake took place just after the installation of a new seismological network by Chilean, German and French researchers. The accelerometric data combined with far field seismic data provide a quite complete and consistent view of the rupture process. The earthquake broke a long (130 km) and narrow (about 30–50 km) zone of the plate interface just above the transition zone. Using a non-linear kinematic inversion method, we determined that rupture occurred on two well-defined patches of roughly elliptical shape. We discuss the consequences of this event for models of gap filling earthquakes in Chile proposed in the 1970s.
To evaluate whether leptin plays a putative role in breast tumorigenesis, we studied the expression of its long and short receptor isoforms in various tumoral breast tissues. We applied ...semiquantitative RT-PCR method to RNA extracted from 20 breast cancer biopsies and two human breast cancer cell lines (T47-D and MCF-7). Our results showed the expression of both leptin receptor transcripts in all tumoral tissues examined. By in situ hybridization experiments, we localized leptin receptors in proliferating epithelial cells. Study of leptin effects on human breast cancer cells growth was performed by
3H-thymidine incorporation method and colorimetric MTT assay. We demonstrated that leptin (50–100 ng/ml) significantly stimulates proliferation of the human breast cancer cell line T47-D (
P<0.05). Western blot analysis indicated that leptin induces a time-dependent activation of mitogen-activated protein kinases (MAPKinase) 1 and 2 in T47-D cell line. Moreover, the specific MAPK-inhibitor PD 98059 blocked cell proliferation induced by leptin. In conclusion, we demonstrate that leptin receptors are expressed in breast cancer and that leptin induces proliferation in the T47-D cell line via activation of the MAPKinases pathway. These data suggest that leptin and its receptors may be implicated in mammary cell proliferation and in breast cancer pathogenesis.
We show here that the neurotrophin nerve growth factor (NGF), which has been shown to be a mitogen for breast cancer cells, also stimulates cell survival through a distinct signaling pathway. Breast ...cancer cell lines (MCF-7, T47-D, BT-20, and MDA-MB-231) were found to express both types of NGF receptors: p140trkA and p75NTR. The two other tyrosine kinase receptors for neurotrophins, TrkB and TrkC, were not expressed. The mitogenic effect of NGF on breast cancer cells required the tyrosine kinase activity of p140trkA as well as the mitogen-activated protein kinase (MAPK) cascade, but was independent of p75NTR. In contrast, the anti-apoptotic effect of NGF (studied using the ceramide analogue C2) required p75NTR as well as the activation of the transcription factor NF-kB, but neither p140trkA nor MAPK was necessary. Other neurotrophins (BDNF, NT-3, NT-4/5) also induced cell survival, although not proliferation, emphasizing the importance of p75NTR in NGF-mediated survival. Both the pharmacological NF-κB inhibitor SN50, and cell transfection with IkBm, resulted in a diminution of NGF anti-apoptotic effect. These data show that two distinct signaling pathways are required for NGF activity and confirm the roles played by p75NTR and NF-κB in the activation of the survival pathway in breast cancer cells.
Large earthquakes produce crustal deformation that can be quantified by geodetic measurements, allowing for the determination of the slip distribution on the fault. We used data from Global ...Positioning System (GPS) networks in Central Chile to infer the static deformation and the kinematics of the 2010 moment magnitude (M w ) 8.8 Maule megathrust earthquake. From elastic modeling, we found a total rupture length of ∼500 kilometers where slip (up to 15 meters) concentrated on two main asperities situated on both sides of the epicenter. We found that rupture reached shallow depths, probably extending up to the trench. Resolvable afterslip occurred in regions of low coseismic slip. The low-frequency hypocenter is relocated 40 kilometers southwest of initial estimates. Rupture propagated bilaterally at about 3.1 kilometers per second, with possible but not fully resolved velocity variations.
We measured the expression of the type I growth factor receptor gene family epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3 and c-erbB-4 in a series of 365 unselected primary breast ...cancers. The expression was quantified with a real-time one-step reverse transcriptase-PCR (RT-PCR) assay, based upon the 5' nuclease activity of the Taq polymerase and using an Abi Prism 7700 Sequence Detector System (Perkin-Elmer, Courtaboeuf, France). c-erbB-3 and c-erbB-4 were positively correlated to each other (Spearman test) and negatively correlated to EGFR. EGFR and c-erbB-2 were inversely correlated to the presence of estradiol receptors (ER) and progesterone receptors (PgR), and positively correlated to the histoprognostic grading (HPG). Conversely, c-erbB-3 and c-erbB-4 were positively correlated to the presence of ER and PgR, and inversely correlated to the grading HPG. EGFR was inversely related (chi2 test) to the presence of ER and PgR, and positively associated with HPG. In contrast, both c-erbB-3 and c-erbB-4 were inversely related to HPG, and positively associated with the presence of ER and PgR. The expression level of EGFR and c-erbB-2 was significantly higher in ER- and PgR-negative tumors compared with ER- and PgR-positive tumors (Student's t test), and in tumors with higher grade compared with tumors with lower grade. The expression level of c-erbB-3 and c-erbB-4 was significantly higher in ER- and PgR-positive tumors compared with ER- and PgR-negative tumors and in tumors with lower grade compared with tumors with higher grade. In overall survival studies, Cox univariate analyses showed prognostic values of EGFR > or = median; P = 0.026; risk ratio (RR), 1.6, c-erbB-3 (> or = median; P = 0.0093; RR, 0.58), c-erbB-4 (> or = median; P = 0.0024; RR, 0.52), HPG, node involvement, tumor diameter, ER, and PgR. In Cox multivariate analyses, tumor diameter, ER, and PgR had a prognostic value. In relapse-free survival studies, univariate analyses demonstrated prognostic values of tumor diameter, node involvement, and c-erbB-4 (P = 0.015; RR, 0.65). These three parameters maintained their prognostic value in multivariate analyses (c-erbB-4, P = 0.035; RR, 0.67). This study confirms that EGFR expression and c-erbB-2 expression are markers of tumor aggressiveness in breast cancer. Conversely, we demonstrate that c-erbB-3 and c-erbB-4 elevated expressions are associated with a better prognosis.
Glyceraldehyde-3-phosphate dehydrogenase (
GAPDH) has been widely used as a control RNA in Northern blotting and in reverse transcriptase–polymerase chain reaction (RT–PCR) analyses. We investigated ...the expression of
GAPDH in a large series of primary breast cancers and in MCF7 human mammary epithelial breast cancer cells treated with oestradiol. The expression of
GAPDH was quantified by a real-time one-step RT–PCR assay, based upon the 5′ nuclease activity of
Taq polymerase using an Abi Prism 7700 Sequence Detector System (Perkin Elmer, France). Using the Spearman test,
GAPDH expression was found to correlate inversely with the age of the patients at diagnosis (
P=0.003;
r=−0.147), oestradiol receptors (ER) (
P<0.0001;
r=−0.327) and progesterone receptors (PgR) (
P<0.0001;
r=−0.206). A positive correlation was observed between
GAPDH expression and the histo-prognostic grading (HPG) (
P<0.0001;
r=0.344). Moreover, the overall survival (OS) and the relapse-free survival (RFS) were significantly reduced in patients whose tumours showed an enhanced level of
GAPDH expression (OS,
P=0.046; RFS,
P=0.021). Multivariate analyses demonstrated that GAPDH was not an independent prognostic factor. Finally, in MCF7 cells treated with oestradiol, a statistically significant dose-dependent increase in
GAPDH expression was observed. These results show that
GAPDH expression is associated with breast cancer cell proliferation and with the aggressiveness of tumours. The present study demonstrates that, in cancer, the use of
GAPDH gene expression should not be used as a control RNA.
Abstract Based on the importance of assessing the true extent of peritoneal disease, PeRitOneal MalIgnancy Stage Evaluation (PROMISE) internet application (www.e-promise.org) has been developed to ...facilitate tabulation and automatically calculate surgically validated peritoneal cancer index (PCI), and other surgically validated scores as Gilly score, simplified peritoneal cancer index (SPCI), Fagotti and Fagotti-modified scores. This application offers computer-assistance to produce simple, quick but precise and standardized pre, intra and postoperative reports of the extent of peritoneal metastases and may help specialized and non-specialized institutions in their current practice but also facilitate research and multicentre studies on peritoneal surface malignancies.
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