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Jean-Philippe Peyrat

Publications and source records attributed to Jean-Philippe Peyrat.

18 recordsLinked to original sources
PubMed2006

Messenger RNA expression of leptin and leptin receptors and their prognostic value in 322 human primary breast cancers.

PURPOSE: Leptin and obesity are clearly related, and obesity is associated with an increased risk of breast cancer. We therefore measured the expression of leptin and its two main receptor isoforms, OBR-L and OBR-S, in 322 breast cancers. We analyzed their relations with the classical prognostic factors and with survival to establish their links with breast cancer. EXPERIMENTAL DESIGN: The expression of leptin and its receptors was quantified by real-time reverse transcription-PCR, using TaqMan fluorogenic probes and an ABI PRISM 7700 sequence detector system (Applied Biosystems, Courtaboeuf, France). TATA box binding protein was used to normalize expression. The human breast cancer cell, SK-BR-3, expressing the three targets, was chosen as the calibrator sample (i.e., target expression = 1). RESULTS: All the tumors expressed both receptors, and 318 of 322 expressed leptin. These three variables correlated positively with each other and with estradiol and progesterone receptors, whereas they correlated negatively with histoprognostic grading and tumor diameter. OBR-L/OBR-S expression was inversely correlated with progesterone receptors. Patients with elevated OBR-S expression had longer relapse-free survival (P = 0.008), whereas high OBR-L/OBR-S was associated with a shorter relapse-free survival (P = 0.05). In Cox multivariate analyses, OBR-S maintained its prognostic value (P = 0.02; relative risk, 0.51). CONCLUSIONS: This study shows that (a) almost all of the breast cancers coexpress leptin and its two main isoforms of receptors, suggesting that the human epithelial breast cancer cells respond to leptin acting via an autocrine pathway; (b) high expression levels of leptin and leptin receptors are biological markers of a more differentiated phenotype; and that (c) OBR-S is an independent prognostic factor.

Adult↗
PubMed2006

Epstein-Barr virus (EBV) genome and expression in breast cancer tissue: effect of EBV infection of breast cancer cells on resistance to paclitaxel (Taxol).

The Epstein-Barr virus (EBV) has been detected in subsets of breast cancers. In order to elaborate on these observations, we quantified by real-time PCR (Q-PCR) the EBV genome in biopsy specimens of breast cancer tissue as well as in tumor cells isolated by microdissection. Our findings show that EBV genomes can be detected by Q-PCR in about half of tumor specimens, usually in low copy numbers. However, we also found that the viral load is highly variable from tumor to tumor. Moreover, EBV genomes are heterogeneously distributed in morphologically identical tumor cells, with some clusters of isolated tumor cells containing relatively high genome numbers while other tumor cells isolated from the same specimen may be negative for EBV DNA. Using reverse transcription-PCR, we detected EBV gene transcripts: EBNA-1 in almost all of the EBV-positive tumors and RNA of the EBV oncoprotein LMP-1 in a smaller subset of the tissues analyzed. Moreover, BARF-1 RNA was detected in half of the cases studied. Furthermore, we observed that in vitro EBV infection of breast carcinoma cells confers resistance to paclitaxel (taxol) and provokes overexpression of a multidrug resistance gene (MDR1). Consequently, even if a small number of breast cancer cells are EBV infected, the impact of EBV infection on the efficiency of anticancer treatment might be of importance.

Adenocarcinoma↗
PubMed2006

TReP-132 is a novel progesterone receptor coactivator required for the inhibition of breast cancer cell growth and enhancement of differentiation by progesterone.

The sex steroid progesterone is essential for the proliferation and differentiation of the mammary gland epithelium during pregnancy. In relation to this, in vitro studies using breast carcinoma T47D cells have demonstrated a biphasic progesterone response, consisting of an initial proliferative burst followed by a sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the progesterone effects on mammary cell growth and differentiation remain to be determined. Recently, it has been demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132), initially identified as a regulator of steroidogenesis, is also a cell growth suppressor. Similar to progesterone-bound PR, TReP-132 acts by inducing the gene expression of the G1 cyclin-dependent kinase inhibitors p21WAF1/Cip1 (p21) and p27Kip1 (p27). The putative interaction between TReP-132 and progesterone pathways in mammary cells was therefore analyzed in the present study. Our results show that TReP-132 interacts in vitro and in T47D cells with progesterone-activated PR. TReP-132 synergizes with progesterone-bound PR to trans activate the p21 and p27 gene promoters at proximal Sp1-binding sites. Moreover, TReP-132 overexpression and knockdown, respectively, increased or prevented the induction of p21 and p27 gene expression by progesterone. As a consequence, TReP-132 knockdown also resulted in the loss of the inhibitory effects of progesterone on pRB phosphorylation, G1/S cell cycle progression, and cell proliferation. Furthermore, the knockdown of TReP-132 expression also prevented the induction of both early and terminal markers of breast cell differentiation which had been previously identified as progesterone target genes. As well, the progesterone-induced accumulation of lipid vacuoles was inhibited in the TReP-132-depleted cells. Finally, TReP-132 gene expression levels increased following progesterone treatment, indicating the existence of a positive auto-regulatory loop between PR and TReP-132. Taken together, these data identify TReP-132 as a coactivator of PR mediating the growth-inhibitory and differentiation effects of progesterone on breast cancer cells.

Binding Sites↗
PubMed2005

Breast cancer risk in BRCA1 and BRCA2 mutation carriers and polyglutamine repeat length in the AIB1 gene.

Marked variation in phenotypic expression among BRCA1 and BRCA2 mutation carriers may be partly explained by modifier genes that influence mutation penetrance. Variation in CAG/CAA repeat lengths coding for stretches of glutamines in the C-terminus of the AIB1 protein (amplified in breast cancer 1, a steroid receptor coactivator) has been proposed to modify the breast cancer risk in women carrying germline BRCA1 mutations. We genotyped the AIB1 repeat length polymorphism from the genomic DNA of a group of 851 BRCA1 and 324 BRCA2 female germline mutation carriers to estimate an association with breast cancer risk modification. Hazard ratios (HR) were calculated using a Cox proportional hazards model. For BRCA1 and BRCA2 mutation carriers, analyzed separately and together, we found that women who carried alleles with 28 or more polyglutamine repeats had no increased risk of breast cancer compared to those who carried alleles with fewer repeats (HR for BRCA1/2 carriers = 0.88, 95% CI [confidence interval] = 0.75-1.04). Analyzing average repeat lengths as a continuous variable showed no excess risk of breast cancer (BC) in BRCA1 or BRCA2 mutation carriers (HR for average repeat length in BRCA1/2 carriers = 1.01, 95% CI = 0.92-1.11). These results strongly suggest that contrary to previous studies, there is no significant effect of AIB1 genetic variation on BC risk in BRCA1 mutation carriers and provide an indication that there is also no strong risk modification in BRCA2 carriers.

Acetyltransferases↗
PubMed2005

Progesterone inhibits human breast cancer cell growth through transcriptional upregulation of the cyclin-dependent kinase inhibitor p27Kip1 gene.

The effects of progesterone derivatives on breast cancer development are still controversial, probably accounting for their biphasic, opposed effects on mammary cell-cycle regulation. Here, we demonstrate in vitro that the growth-inhibitory effects of progesterone on breast cancer T-47D cells require the transcriptional upregulation of the cyclin-dependent kinase inhibitor p27(Kip1) (p27) gene. A statistical analysis of human tumor biopsies further indicates that p27 mRNA levels correlate to progesterone receptor (PR) levels. Moreover, p27 gene expression is inversely associated with tumor aggressiveness, and is a prognostic factor of favorable disease outcome. Thus, progesterone derivatives selectively activating the p27 gene promoter could be promising drugs against breast cancer progression.

Breast Neoplasms↗
PubMed2005

Expression and prognostic value of lactoferrin mRNA isoforms in human breast cancer.

We investigated the expression levels of human lactoferrin (Lf), a steroid hormone-inducible gene product the expression of which is often altered during oncogenesis, and of Delta-lactoferrin (DeltaLf), its alternative isoform, which has been shown to be absent from tumor cell lines in commonly used human breast epithelial cell lines, using semiquantitative RT-PCR. Both mRNAs were detected but with levels of expression lower than those found in normal breast epithelial cells. This downregulation was much more visible for DeltaLf since its expression was either significantly diminished (BT-20, MCF-7 cell lines) or practically absent (MDA-MB-231, T-47D, HBL 100 cell lines). In order to determine whether Lf gene products are useful prognosic tools, we further analyzed their expression levels in 99 primary breast cancer biopsies. DeltaLf transcripts were found in all of the samples, whereas Lf transcripts were found in 88% of them. Lf and DeltaLf expression levels were positively correlated (p = 0.003). Lf expression was related to tumor type with a higher recovery in lobular-type tumors (p = 0.04). DeltaLf expression was related to the histoprognostic grading (p = 0.02). In univariate analyses, DeltaLf and Lf expressions were prognosis parameters, high concentrations being associated with a longer overall survival.

Base Sequence↗
PubMed2005

TReP-132 controls cell proliferation by regulating the expression of the cyclin-dependent kinase inhibitors p21WAF1/Cip1 and p27Kip1.

The transcriptional regulating protein of 132 kDa (TReP-132) has been identified in steroidogenic tissues, where it acts as a coactivator of steroidogenic factor 1 (SF-1). We show here that TReP-132 plays a role in the control of cell proliferation. In human HeLa cells, TReP-132 knockdown by using small interfering RNA resulted in increased G(1)-->S cell cycle progression. The growth-inhibitory effects of TReP-132 was further shown to be mediated by induction of G(1) cyclin-dependent kinase inhibitors p21(WAF1) (p21) and p27(KIP1) (p27) expression levels. As a consequence, G(1) cyclin/cyclin-dependent kinase activities and pRB phosphorylation were markedly reduced, and cell cycle progression was blocked in the G(1) phase. The stimulatory effect of TReP-132 on p21 and p27 gene transcription involved interaction of TReP-132 with the transcription factor Sp1 at proximal Sp1-binding sites in their promoters. Moreover, in different breast tumor cell lines, endogenous TReP-132 expression was positively related with a lower proliferation rate. In addition, TReP-132 knockdown resulted in enhanced cell proliferation and lowered p21 and p27 mRNA levels in the steroid-responsive and nonresponsive T-47D and MDA-MB-231 cell lines, respectively. Finally, a statistic profiling of human breast tumor samples highlighted that expression of TReP-132 is correlated with p21 and p27 levels and is associated with lower tumor incidence and aggressiveness. Together, these results identify TReP-132 as a basal cell cycle regulatory protein acting, at least in part, by interacting with Sp1 to activate the p21 and p27 gene promoters.

Breast Neoplasms↗
PubMed2005

Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers.

The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.

Adult↗
PubMed2004

Prognostic value of ERM gene expression in human primary breast cancers.

We measured the expression of ERM gene, a nuclear transcription factor belonging to the ets family, in a series of 364 unselected primary breast cancers from patients who underwent locoregional surgery in the Centre Oscar Lambret between May 1989 and December 1991. The expression of ERM was quantified with a real-time one-step reverse transcription-PCR assay based on the 5'-nuclease activity of the TaqDNA polymerase and with an Abi Prism 7700 Sequence Detector System (Applied Biosystems, Courtaboeuf, France). ERM was positively correlated (Spearman test) to epidermal growth factor receptor (EGFR; P < 0.001, r = 0.296) and to histoprognostic grading (P = 0.044, r = 0.112), whereas it was negatively correlated to estradiol receptors (P = 0.019, r = -0.124), HER3 (c-erbB-3; P = 0.01, r = -0.135), and HER4 (c-erbB-4; P = 0.003, r = -0.154). Using the chi2 test, a positive relationship was found between the expression of ERM and EGFR (chi2 = 7.795, P = 0.007). In overall survival studies, Cox univariate analyses demonstrated a prognostic value of ERM (P = 0.006; risk ratio, 2.95) besides the classical prognostic factors histoprognostic grading, node involvement, tumor size, estradiol receptors, progesterone receptors, EGFR, HER3, and HER4. In multivariate analyses, ERM preserved its prognostic value (P = 0.004; risk ratio, 3.779) together with histoprognostic grading, tumor size, estradiol receptors, and progesterone receptors. In relapse-free survival studies, univariate analyses demonstrated that histoprognostic grading, node involvement, tumor size, and HER4 were prognostic factors. These parameters, except histoprognostic grading, retained their prognostic value in multivariate analyses. This study demonstrates for the first time that ERM gene expression is an independent adverse prognostic factor for overall survival in breast cancer patients.

Adult↗
PubMed2004

Association between systemic sclerosis and breast cancer: eight new cases and review of the literature.

Several studies have demonstrated an increased frequency of cancer in patients with systemic sclerosis (SSc), specially lung and breast cancers. The pathogenesis of the association between SSc and cancer is not fully established. The aim of this study was to describe new cases of the association between SSc and breast cancer and to perform a review of the literature. We retrospectively studied the medical files of eight patients followed in our institution for SSc and breast cancer. We analyzed them with data available in the literature for a total of 46 patients. Cutaneous extension of SSc was clearly mentioned in 17 cases: the SSc was limited in 10 cases and diffuse in 7 cases The median age at the diagnosis of cancer was 54 years (range: 40-71). The median duration between SSc onset and breast cancer diagnosis was 11.5 months (range: 0-288). The duration between SSc onset and breast cancer diagnosis was < or = 12 months in 27 of 44 patients (61.4%), and in 11 (25%) of them the diagnosis of both diseases was made simultaneously. It was clearly mentioned for 35 patients whether the diagnosis of breast cancer was made before or after the onset of SSc. The diagnosis of breast cancer was made before SSc onset in 17 of 35 patients (48.6%) and after SSc onset in 18 of 35 patients (51.4%). For 33 patients, the follow-up was available: 18 (54.5%) died, 11 (33.3%) of them within the 1st year after the diagnosis of the cancer. For none of the patients did the anticancer treatment improve the SSc. The close temporal relationship between SSc onset and breast cancer diagnosis is highly suggestive of a pathophysiological link. SSc is probably not a paraneoplastic disease since the anticancer treatment has no influence on the evolution of SSc. However, it can be suggested that SSc could be a disease facilitating breast cancer and/or metastases development.

Adult↗
PubMed2004

Multiplex reverse transcription polymerase chain reaction assessment of sialyltransferase expression in peripheral blood mononuclear cells in systemic sclerosis.

OBJECTIVE: To assess sialyltransferase expression in peripheral blood mononuclear cells (PBMC) of patients with systemic sclerosis (SSc) and to correlate this expression with the clinical features of the disease. METHODS: Using a multiplex reverse transcription polymerase chain reaction (RT-PCR) method, we simultaneously measured the expression of 5 sialyltransferases (ST3Gal IV, ST3Gal III, ST3Gal I, ST3Gal II, and ST6Gal I) and of one reference housekeeping gene, Tata box binding protein (TBP), in PBMC of 28 patients with SSc and 18 healthy controls. Expression of each sialyltransferase was defined by the ratio sialyltransferase amplification product intensity/TBP amplification product intensity, and was evaluated according to the skin sclerosis extension and the presence of lung fibrosis and/or of pulmonary hypertension. RESULTS: ST3Gal I and ST6Gal I expressions were lower in patients with SSc than in healthy controls (median 0.48 vs 1.30, p < 0.0001, and 0.71 vs 1.96, p < 0.01, respectively). No difference was observed for ST3Gal III and ST3Gal IV expression. ST3Gal IV/ST6Gal I ratio was higher in SSc patients than in controls (0.37 vs 0.28, p = 0.03). ST3Gal II was either weakly or more often not expressed in both groups. Ten patients had isolated pulmonary hypertension. They had higher ST3Gal IV expression than patients without pulmonary hypertension (0.73 vs 0.29, p = 0.04) and a higher ST3Gal IV/ST6Gal I ratio than patients without pulmonary hypertension (1.03 vs 0.27, p = 0.03) and controls (1.03 vs 0.28, p = 0.02). No difference was found in the sialyltransferase expression and soluble E-selectin concentration according to the cutaneous sclerosis extension or the presence of lung fibrosis. CONCLUSION: Sialyltransferase expression is modified in PBMC of patients with SSc compared to healthy subjects. Low ST6Gal I expression associated with normal ST3Gal IV expression, resulting in a higher ST3Gal IV/ST6Gal I ratio, suggests an enhanced expression of Sialyl-LewisX at the surface of PBMC in SSc, and therefore an active interaction between activated endothelial cells and PBMC through the binding between E-selectin and Sialyl-LewisX. This suggested that higher expression of Sialyl-LewisX concerned patients with isolated pulmonary hypertension more specifically. Binding between PBMC surface Sialyl-LewisX and activated endothelial cell E-selectin might therefore play a role in the pathogenesis of SSc-related isolated pulmonary hypertension.

Adult↗
PubMed2003

Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients.

In this report we present an extension of the pooled analysis of the prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I in breast cancer patients. We analyzed a different endpoint, metastasis-free survival (MFS). We checked the consistency of the estimates for uPA and PAI-1 for relapse-free survival (RFS) and MFS exploring possible sources of heterogeneity. Nodal status, the most important prognostic factor for breast cancer, introduced heterogeneity in the uPA/PAI-1 survival analyses, reflecting the interaction between nodal status and uPA/PAI-1. The estimates for uPA and PAI-1 were found to be consistent, even when a different transformation of their values was used. The heterogeneity of the separate data sets decreased if the levels of uPA and PAI-1 were ranked, data sets were pooled, and the analyses corrected for the base model that included all traditional prognostic factors, and stratified by data set. We conclude that uPA and PAI-1 are ready to be used in the clinic to help classify breast cancer patients into high and low risk groups.

Breast Neoplasms↗
PubMed2003

BRCA1 wild-type allele modifies risk of ovarian cancer in carriers of BRCA1 germ-line mutations.

Strong inter- and intrafamilial variation of penetrance of breast and ovarian cancer is observed in BRCA1 mutation carriers. The wild-type copy of the BRCA1 gene is a plausible candidate as a cancer risk modifier given that the residual function corresponding to the intact BRCA1 allele may influence the process of tumor formation in BRCA1 carriers. Indeed, growing evidence is now becoming available on impaired reparation of double-strand DNA breaks in cells heterozygous for BRCA1 mutations, implying an enhanced mutability of BRCA1(+/-) cells. To determine whether certain variant forms of the wild-type BRCA1 allele are implicated in variation of the BRCA1-related cancer risk, their effect was studied in a panel of 591 women with BRCA1 germ-line mutations. We found that BRCA1 carriers with the wild-type BRCA1 copy bearing a common Gly1038 variant were at increased risk of ovarian cancer (hazards ratio, 1.50; 95% confidence interval, 1.03-2.19). The results of our study imply that a quite significant proportion of the interindividual variability in ovarian cancer penetrance in BRCA1 carriers may be explained by a common BRCA1 Gly1038 wild-type allele, given its high frequency (0.27).

Adult↗
PubMed2003

[Inhibitors of epidermal growth factor receptor and colorectal cancer].

Colorectal cancers (CRC) express the epidermal growth factor receptor (EGF-R), a type I transmembrane receptor with tyrosine kinase activity. EGF-R signaling inhibition is a promising target for cancer therapy. ZD1839 (Iressa, AstraZeneca) and OSI-774 (Tarceva, Roche) are small molecular weight molecules with selective and reversible tyrosine kinase inhibition properties directed to EGF-R. Orally administered, these molecules induce sustained tumor stabilizations in previously treated metastatic CRC patients. The most frequent treatment-related toxicities are fatigue, diarrhea and acne-like follicular rash. The addition in the clinic of 5-FU, lOHP or CPT-11 to ZD1839 or OSI-774 does not seem to increase the own toxicity of each cytotoxic agents. Cetuximab (Erbitux, Merck) is an intravenously administered humanized monoclonal antibody which bind with high affinity with the extracellular domain of the EGF-R. The most frequent treatment-related toxicities are diarrhea, fatigue, nausea and cutaneous toxicity (allergic or acne-like follicular rashes, folliculitis). Most, if not all of these adverse events are mild. Partial responses were observed with cetuximab either alone (RR: 10%) or in combination with CPT-11 (RR: 22%) in patients with CPT-11 refractory advanced CRC which expressed EGF-R. The combination of cetuximab to folinic acid, 5-FU and CPT-11 seems tolerable at the cost of a slight increase of severe diarrhea and neutropenia. Finally, the promising activity of these EGF-R inhibitors has to be confirmed throughout randomized studies.

Antineoplastic Agents↗
PubMed2002

Cross-talk between mesenchyme and epithelium increases H19 gene expression during scattering and morphogenesis of epithelial cells.

The H19 gene is an imprinted gene expressed from the maternal allele. It is known to function as an RNA molecule. We previously reported that in breast adenocarcinoma, H19 is often overexpressed in stromal cells and preferentially located at the epithelium/stroma boundary, suggesting that epithelial/mesenchymal interactions can control H19 RNA expression. In some cases of breast adenocarcinoma with poor prognosis, H19 is overexpressed in epithelial cells. Therefore we examined whether mesenchymal factors can induce H19 expression in epithelial cells. Using quantitative RT-PCR and in situ hybridization, we found that when mammary epithelial cells were cultured in collagen gels, H19 expression was strongly up-regulated compared to when cells were cultured on plastic. Collagen gels allow three-dimensional growth of epithelial cells and morphogenetic responses to soluble factors. A conditioned medium from MRC-5 fibroblasts caused branching morphogenesis of HBL-100 cells and invasive growth of MDA-MB-231 cells, whereas MCF-7 cells were unresponsive. Induction of H19 expression correlated with morphological changes in HBL-100 and in MDA-MB-231 cells, whereas H19 expression was not induced in MCF-7 cells. Using a blocking antibody, HGF/SF was identified as the fibroblast-derived growth factor capable of inducing H19 expression and cell morphogenesis. We further demonstrated that H19 promoter activity was stimulated by various growth factors using transient transfection in MDCK epithelial cells. HGF/SF was more efficient than EGF or FGF-2 in transactivating the H19 promoter, whereas IGF-2, TGFbeta-1, and TNF-alpha were ineffective. This activation by HGF/SF was prevented by pharmacological inhibition of MAP kinase or of phospholipase C. We conclude that H19 is a target gene for HGF/SF, a known regulator of epithelial/mesenchymal interactions, and suggest that the up-regulation of H19 may be implicated in morphogenesis and/or migration of epithelial cells.

Animals↗
PubMed2002

Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients.

BACKGROUND: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). METHODS: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. RESULTS: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). CONCLUSIONS: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategies.

Adult↗
PubMedDate not supplied

mRNA expression of the type I growth factor receptors in the human breast cancer cells MCF-7: regulation by estradiol and tamoxifen.

BACKGROUND: We recently confirmed, in a series of 365 human breast cancers, that EGFR and c-erbB-2 were associated with estradiol receptors (ER) and/or progesterone receptors (PgR)-negative tumors. Conversely, we demonstrated that c-erbB-3 and c-erbB-4 were positively related to ER and PgR. In the present paper, we simultaneously quantified, for the first time, the mRNA expression of these four receptors in response to estradiol and 4-hydroxy-tamoxifen in the prototypical ER-positive human breast cancer cell line MCF-7. MATERIALS AND METHODS: The mRNA expression of the type I growth factor receptors was quantified with a one-step real-time RT-PCR assay. RESULTS: Estradiol down-regulates the mRNA expression of the four receptors. The EGFR decrease is maximal (30% under the control) for 10(-11) M estradiol. For the three other receptors, the decrease (50% under the control) in mRNA expression is maximal with 10(-9) M. These effects are completely abolished by 4-OH tamoxifen at 10(-6) M. CONCLUSION: In MCF-7 cells, we demonstrate that c-erbB-4 is down-regulated by estradiol and up-regulated by 4-OH tamoxifen, and confirm that the three other receptors followed the same pattern of expression.

Adenocarcinoma↗