Biomedical subjects

J P Peyrat

Publications and source records attributed to J P Peyrat.

At least 19 recordsLinked to original sources

PubMed2002

Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line.

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.

Blotting, Western↗

PubMed2001

Expression of nerve growth factor receptors and their prognostic value in human breast cancer.

Nerve growth factor (NGF) has been shown recently to be mitogenic for human breast cancer cells. In the present study, we have assayed the expression of NGF receptors (NGFRs: TrkA and p75) mRNAs in 363 human primary breast cancers, using real-time quantitative reverse transcription-PCR. NGFRs were found in all of the tumor biopsies. TrkA and p75 were positively correlated and were respectively associated with the histoprognostic grading and the tumor type. NGFRs were both related to progesterone receptors. In univariate analyses, TrkA (>upper quartile) was associated with longer overall survival. Histoprognostic grading, tumor size, node involvement, and steroid receptors were also prognostic factors. In Cox multivariate analyses, TrkA was not a prognostic parameter. This study demonstrates the expression of NGFRs in breast cancer and points out that patients with high levels of TrkA have a more favorable overall survival prognosis.

Adult↗

PubMed2001

Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways.

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: p140(trkA) and p75(NTR). 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 p140(trkA) as well as the mitogen-activated protein kinase (MAPK) cascade, but was independent of p75(NTR). In contrast, the anti-apoptotic effect of NGF (studied using the ceramide analogue C2) required p75(NTR) as well as the activation of the transcription factor NF-kB, but neither p140(trkA) nor MAPK was necessary. Other neurotrophins (BDNF, NT-3, NT-4/5) also induced cell survival, although not proliferation, emphasizing the importance of p75(NTR) in NGF-mediated survival. Both the pharmacological NF-kappaB 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 p75(NTR) and NF-kappaB in the activation of the survival pathway in breast cancer cells.

Breast Neoplasms↗

PubMed2001

Proteomic detection of changes in protein synthesis induced by fibroblast growth factor-2 in MCF-7 human breast cancer cells.

Fibroblast growth factor-2 (FGF-2) is a potent regulator of breast cancer cell growth through stimulation of tyrosine kinase receptors and activation of the mitogen-activated protein kinase cascade. In the present study, we have investigated changes in protein synthesis induced by FGF-2 stimulation of the prototypic human breast cancer cell line MCF-7. Using high-resolution two-dimensional electrophoresis of (35)S amino acid metabolically labeled proteins and computerized analysis of 2D autoradiograms, we found that four proteins were up-regulated within the first 12 h of FGF-2 stimulation. Mass spectrometry analysis (MALDI-TOF and MS-MS) of tryptic fragments and database searches allowed the identification of these FGF-2-regulated proteins as the heat shock proteins HSP90 and HSP70, the proliferating cell nuclear antigen (PCNA), and the transcriptionaly controlled tumor protein (TCTP). We then analyzed the distribution of these proteins in various cancerous and normal breast epithelial cells. Interestingly, the four FGF-2-regulated proteins were found to be constitutively up-regulated in ras-transfected MCF-7 cells, indicating their relevance to the up-regulation of cellular proliferation. Moreover, HSP90 and PCNA were found at higher levels in cancerous cells than in normal cells. The role of HSP90 was further investigated using the specific inhibitor geldanamycin. We showed that the functionality of HSP90 is strictly required in order to obtain FGF-2 mitogenic stimulation in MCF-7 cells, indicating the crucial role played by this molecular chaperone in the control of breast cancer cell growth. Finally, these results show that proteomic analysis is a valuable method for identifying potential markers or therapeutic targets related to cancer growth.

Biomarkers, Tumor↗

PubMed2001

Proteomic analysis reveals that 14-3-3sigma is down-regulated in human breast cancer cells.

The class of molecular chaperones known as 14-3-3 is involved in the control of cellular growth by virtue of its apparent regulation of various signaling pathways, including the Raf/mitogen-activated protein kinase pathway. In breast cancer cells, the sigma form of 14-3-3 has been shown to interact with cyclin-dependent kinases and to control the rate of entry into mitosis. To test for a direct role for 14-3-3 in breast epithelial cell neoplasia, we have quantitated 14-3-3 protein levels using a proteomic approach based on two-dimensional electrophoresis and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF). We show here that 14-3-3sigma protein is strongly down-regulated in the prototypic breast cancer cell lines MCF-7 and MDA-MB-231 and in primary breast carcinomas as compared with normal breast epithelial cells. In contrast, levels of the alpha, beta, delta, or zeta isoforms of 14-3-3 were the same in both normal and transformed cells. The data support the idea that 14-3-3sigma is involved in the neoplastic transition of breast epithelial cells by virtue of its role as a tumor suppressor; as such, it may constitute a robust marker with clinical efficacy for this pathology.

14-3-3 Proteins↗

PubMed2001

Proteomics of breast cancer for marker discovery and signal pathway profiling.

Breast cancer is the most common form of cancer among women and the identification of markers to discriminate tumorigenic from normal cells, as well as the different stages of this pathology, is of critical importance. Two-dimensional electrophoresis has been used before for studying breast cancer, but the progressive completion of human genomic sequencing and the introduction of mass spectrometry, combined with advanced bioinformatics for protein identification, have considerably increased the possibilities for characterizing new markers and therapeutic targets. Breast cancer proteomics has already identified markers of potential clinical interest (such as the molecular chaperone 14-3-3 sigma) and technological innovations such as large scale and high throughput analysis are now driving the field. Methods in functional proteomics have also been developed to study the intracellular signaling pathways that underlie the development of breast cancer. As illustrated with fibroblast growth factor-2, a mitogen and motogen factor for breast cancer cells, proteomics is a powerful approach to identify signaling proteins and to decipher the complex signaling circuitry involved in tumor growth. Together with genomics, proteomics is well on the way to molecularly characterizing the different types of breast tumor, and thus defining new therapeutic targets for future treatment.

14-3-3 Proteins↗

PubMed2001

Expression of BRCA1 gene in ewe mammary epithelial cells during pregnancy: regulation by growth hormone and steroid hormones.

OBJECTIVE: Steroid hormones (estradiol and progesterone) in association with prolactin and growth hormone are involved in lobulo alveolar development of the mammary gland during pregnancy. We hypothesized that the BRCA1 gene may be induced by these different hormones. METHODS AND RESULTS: In this study, we have demonstrated by Northern blot and in situ hybridization, that the expression of ovine (o) BRCA1 mRNA in mammary epithelial cells increased dramatically during a short period in the second half of pregnancy (days 70 to 112) and decreased at the end of pregnancy. The increase in oBRCA1 mRNA expression is concomitant with rapid lobulo alveolar growth. Using an in vivo protocol to artificially induce mammary gland development, we demonstrated by the real-time RT-PCR method that growth hormone in association with estrogen, progesterone and hydrocortisone induces an increase of BRCA1 mRNA expression in the ewe mammary gland. Moreover, we showed that estradiol and progesterone induce oBRCA1 expression in primary cultures of ewe mammary gland. CONCLUSIONS: These results suggest that BRCA1 is a potential regulator of the effects of steroid hormones and growth hormone in the induction of mammary epithelial cell proliferation.

Animals↗

PubMed2001

[Proteomic analysis: why and how ?].

The proteome, first formalized in 1995, designs all the proteins expressed by the genome of a cell, tissu, or organ at a defined time. Proteomic analysis leads to a description of the regulation of gene expression by the study of proteins and of their post-translational modifications. Proteomic analysis is based on three technologies: 1) Two-dimensional electrophoresis allowing the separation of thousands of proteins from a single mixture; 2) mass spectrometry allowing the characterization of picoquantities of polypeptides and providing data on post-translational modifications; 3) Bioinformatic which is required for the quantification of protein level and for the constitution of databases of protein expression profiles. Complementing the methods of the genomics, the use of proteomic analysis is widely spreading in the fields of fundamental biology, biomedicine and pharmacology for the identification of new biological markers and therapeutic targets.

Animals↗

PubMed2000

Characterization and modulation of a prolactin receptor mRNA isoform in normal and tumoral human breast tissues.

The role of prolactin (PRL) and its specific receptor (R-PRL) in human breast tumorigenesis remains unclear. We have investigated here the presence of extracellular-deleted hPRL-R isoforms in normal human breast, fibrocystic disease, primary breast carcinoma (ductal carcinoma, ductulo-lobular and lobular) and breast cancer cell lines (T47-D and MCF-7). RT-PCR and Southern blot analysis demonstrated the expression of full-length hPRL-R transcript in all samples tested. We also detected a hPRL-R transcript generated by alternative exon 6 splicing. This isoform has a 170 bp deletion in its extracellular sub-domain that induces a frameshift. Thus, the predicted amino-acid sequence should encode a putative soluble protein with the N-terminal sub-domain of the hPRL-R and 10 additional carboxy-terminal residues. This isoform should not bind PRL as previously demonstrated by other experiments. Moreover, the ratio of full-length to deleted form of hPRL-R transcripts differs from normal to tumoral breast tissue. This ratio is higher in tumoral mammary gland than in normal tissue. Our data suggest that the alternative splicing of the hPRL-R gene towards the deleted transcript may be a mechanism to down- or up-regulate the expression of the native transcript of hPRL-R in accordance to the physiological or pathological state of the mammary gland.

Amino Acid Sequence↗

PubMed2000

Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis.

OBJECTIVE: Endostatin is an angiogenesis inhibitor derived from type XVIII collagen. The aim of this study was to determine the concentrations of circulating endostatin in patients with systemic sclerosis (SSc), and to assess the relationship between these concentrations, extension of tissular sclerosis, and presence of cutaneous scars or ulcers. METHODS: The study involved 50 patients with SSc and 30 healthy subjects. Cutaneous extension of sclerosis was graded according to Barnett's classification system: 33 patients had grade I SSc and 17 patients had grades II or III SSc. The results of pulmonary function tests were abnormal in 31 of 50 patients, 8 of whom also had abnormalities on chest radiograms. Cutaneous scars or ulcers were found in 22 of 50 patients. Endostatin concentrations were determined using a competitive enzyme immunoassay method. RESULTS: The mean circulating endostatin concentration was significantly higher in the SSc group than in the healthy subjects group (mean +/- SD 53.2 +/- 22.4 ng/ml versus 9.9 +/- 9.7 ng/ml; P < 10(-4)), in patients with grade II or grade III SSc than in patients with grade I SSc (63.2 +/- 20.2 ng/ml versus 45.1 +/- 15.6 ng/ml; P < 10(-2)), in patients with abnormal findings on chest radiograms than in patients with normal findings on chest radiograms (67.6 +/- 22.4 ng/ml versus 50.4 +/- 21.6 ng/ml; P < 0.05), and in patients with cutaneous scars or ulcers than in patients without these manifestations (60.9 +/- 25.9 ng/ml versus 47.2 +/- 13.3 ng/ml; P < 10(-2)). CONCLUSION: Circulating endostatin concentrations are significantly increased in patients with SSc. Production of endostatin may result from tissular sclerosis and could contribute to the development of ischemic manifestations.

Adult↗

PubMed2000

Regulation of sialyltransferase expression by estradiol and 4-OH-tamoxifen in the human breast cancer cell MCF-7.

We have addressed the effects of estradiol and 4-OH-tamoxifen on the expression of five sialyltransferases in the hormono-dependent MCF-7 cell line using a Multiplex RT-PCR approach. Estradiol induced a statistically significant increase in ST3Gal III and a decrease in ST6Gal I, whereas the two other enzymes, ST3Gal IV and ST3Gal I, are not modified and expression of the fifth enzyme, ST3Gal II, was very low or not detectable. Estradiol effects were dose dependent and completely antagonized by 4OH-tamoxifen. In addition, there is no direct relation between cellular proliferation and sialyltransferase expression. This suggests that ST3Gal III and ST6Gal I could be used as supplementary markers of hormono-sensitivity in breast cancer.

Antineoplastic Agents, Hormonal↗

PubMed2000

Glyceraldehyde-3-phosphate dehydrogenase gene expression in human breast cancer.

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.

Adult↗

PubMed2000

Bcl-2/Bax protein ratio predicts 5-fluorouracil sensitivity independently of p53 status.

p53 tumour-suppressor gene is involved in cell growth control, arrest and apoptosis. Nevertheless cell cycle arrest and apoptosis induction can be observed in p53-defective cells after exposure to DNA-damaging agents such as 5-fluorouracil (5-FU) suggesting the importance of alternative pathways via p53-independent mechanisms. In order to establish relationship between p53 status, cell cycle arrest, Bcl-2/Bax regulation and 5-FU sensitivity, we examined p53 mRNA and protein expression and p53 protein functionality in wild-type (wt) and mutant (mt) p53 cell lines. p53 mRNA and p53 protein expression were determined before and after exposure to equitoxic 5-FU concentration in six human carcinoma cell lines differing in p53 status and displaying marked differences in 5-FU sensitivity, with IC(50)values ranging from 0.2-22.6 mM. 5-FU induced a rise in p53 mRNA expression in mt p53 cell lines and in human papilloma virus positive wt p53 cell line, whereas significant decrease in p53 mRNA expression was found in wt p53 cell line. Whatever p53 status, 5-FU altered p53 transcriptional and translational regulation leading to up-regulation of p53 protein. In relation with p53 functionality, but independently of p53 mutational status, after exposure to 5-FU equitoxic concentration, all cell lines were able to arrest in G1. No relationship was evidenced between G1 accumulation ability and 5-FU sensitivity. Moreover, after 5-FU exposure, Bax and Bcl-2 proteins regulation was under p53 protein control and a statistically significant relationship (r = 0.880, P = 0.0097) was observed between Bcl-2/Bax ratio and 5-FU sensitivity. In conclusion, whatever p53 status, Bcl-2 or Bax induction and Bcl-2/Bax protein ratio were correlated to 5-FU sensitivity.

Adenocarcinoma↗

PubMed2000

A real-time one-step reverse transcriptase-polymerase chain reaction method to quantify c-erbB-2 expression in human breast cancer.

We developed a real-time one-step reverse transcriptase-polymerase chain reaction (RT-PCR) method for the routine quantification of c-erbB-2 oncogene expression in breast cancer, using a 7700 ABI PRISM Sequence Detector System (Perkin Elmer-Applied Biosystems, Courtaboeuf, France). The real-time quantification of the polymerase chain reaction products is based on the TaqMan 5' nuclease assay. The optimal experimental conditions we determined were as follows: 6 mM MgCl2, 200 nM of fluorogenic probe, 200 nM of each primer, and 12.5 units MuLV reverse transcriptase. The GAPDH housekeeping gene was used for normalization of c-erbB-2 expression. In human breast cancer cell lines, the normalized expression of c-erbB-2 ranged from 8 x 10(-6) to 2,600 x 10(-6), the two highest values corresponding to the c-erbB-2 overexpressing cells MDA-MB-453 and SK-BR-3. In a series of 100 breast cancer samples, c-erbB-2 normalized expression was found to range from 0.4 x 10(-6) to 350 x 10(-6). A close correlation was observed between this real-time one-step quantitative RT-PCR method and both semiquantitative conventional RT-PCR (N = 22; r = 0.8543; P < .0001) and c-erbB-2 protein expression (p185) quantified by an enzyme immunoassay (EIA) (N = 27; r = 0.71; P < .0001). The current realtime RT-PCR assay is rapid, sensitive, and reproducible and appears particularly suitable to quantify gene expression in large series of samples.

Breast Neoplasms↗

PubMed2000

Prognostic value of the type I growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay.

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.

Adult↗

PubMed1999

Histological type and syncytial growth pattern affect E-cadherin expression in a multifactorial analysis of a combined panel of sporadic and BRCA1-associated breast cancers.

E-cadherin is a prominent factor in maintaining the epithelial architecture, and loss of its normal function is considered to be a key element in cancer invasion. In breast cancer, correlation between alteration of E-cadherin expression and histological type has been reported, but associations with other parameters remain uncertain. To refine these findings and to explore the biological significance of features thought to result from alterations of cell-to-cell adhesion systems, rare in sporadic cases but more frequent in BRCA1-associated breast cancers (BRCA1-BCs), we investigated E-cadherin expression by immuno-histochemistry in a combined panel of 214 breast cancers enriched in hereditary cases (176 sporadic cases and 38 BRCA1-BCs). Following multivariate statistical analysis using a logistic regression model, only 2 parameters were significantly associated with loss of E-cadherin expression: lobular histological type (p < 0.0001), in agreement with previous results, and syncytial growth pattern (SGP) (p = 0.01). The latter result provides a biological basis for SGP, the cardinal feature of medullary breast carcinoma.

BRCA1 Protein↗

PubMed1999

Novel indications for BRCA1 screening using individual clinical and morphological features.

Since there is a lack of common family profile among BRCA1-gene carriers, and since the risk of being a mutation carrier is not limited to women with a family history of breast or ovarian cancer, multivariate statistical analysis using the logistic-regression model was carried out, to discriminate between sporadic cases and BRCA1-breast cancers (BRCA1-BCs), especially when information about the family history of breast/ovarian cancer and ethnicity are irrelevant or unavailable, in order to offer specific medical treatment to this population. We examined 32 BRCA1-BCs selected at cancer genetic clinics and 200 consecutive controls without family history of breast cancer for age at onset and current morphological parameters. Following the multivariate analysis, 3 parameters only, namely, early age at cancer onset [odds ratio (OR) for each year = 1.16; p < 0.0001], estrogen-receptor negativity (OR = 5.7; p = 0.01) and poor differentiation (OR = 5; p = 0.03) were found significant factors for predicting BRCA1-carrier status. The expected impact in BRCA1 screening of our model was estimated using data on 5700 breast-cancer cases from a hospital-based registry. Only 50 and 15% of tumours with early age at onset below 35 years present one or the other 2 discriminant parameters respectively. Consequently, whereas the probability of finding a BRCA1 mutation is rated low (6.2%) when the sole criterion of early onset up to the age of 35 years is used, based on our model, in the sub-group of women with a tumor that is both estrogen-receptor-negative and poorly differentiated the mutation-detection rate is predicted to be above the 10% chance level recommended by the ASCO guidelines. This sub-group of women, representing about 1% of all breast-cancer cases in Western countries, consequently deserves to be tested.

Adult↗

PubMed1999

Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro.

Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans- and 9-cis-retinoic acid, as well as the retinoic acid receptor gamma (RAR-gamma) selective agonists CD2325 and CD437 (1 microM), were able to down-regulate prolactin receptor. After 1 h, a significant reduction was detectable and maximal effect was achieved after 24 h of treatment. Pretreatment with retinoic acid also reduced the prolactin-/prolactin receptor-dependent signal transduction and activation of transcription 5 (STAT-5) activation in T47D cells. Cycloheximide failed to abrogate the retinoic acid-induced decline in prolactin receptor mRNA levels, indicating that this effect was not dependent upon continuing protein synthesis. Similarly, no change in the stability of prolactin receptor mRNA was observed during 12 h of retinoic acid treatment. In conclusion, our results demonstrate that retinoids are able to inhibit the expression of prolactin receptor message, which encodes an important growth factor receptor in breast cancer cells. This action could be responsible for the anti-tumour effects of retinoids.

Alitretinoin↗