HSD3B1 (1245A>C) germline variant and clinical outcomes in metastatic castration-resistant prostate cancer patients treated with abiraterone and enzalutamide: results from two prospective studies.

BACKGROUND: A common polymorphism (1245A>C) in the HSD3B1 gene is associated with increased de novo synthesis of androgens and worse outcomes in men treated with androgen-deprivation therapy for metastatic castration-sensitive prostate cancer. The objective of the study was to determine whether this polymorphism is associated with outcomes for metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide. PATIENTS AND METHODS: A total of 547 patients treated with abiraterone or enzalutamide from two prospective cohorts were evaluated. The HSD3B1 genotype was determined by targeted sequencing and/or TaqMan single-nucleotide polymorphism genotyping. In cohort 1, patients were randomized to receive abiraterone + prednisone or enzalutamide. In cohort 2, patients received either agent according to investigator's choice. Prostate-specific antigen (PSA) response rate, time to PSA progression (TTPP), time to progression (TTP) and overall survival were determined. Associations between HSD3B1 genotypes and outcomes were evaluated via univariate Cox regression. Multivariable Cox model was used to determine the independent association of each covariate. RESULTS: The HSD3B1 variant genotype (CC) was present in 15% of patients and was associated with worse TTP [hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.02-1.67, P = 0.032] and PSA response rates (48% for CC versus 62% and 65% for AA and AC, respectively [P = 0.019]), with no significant difference in TTPP (HR 1.28, 95% CI 0.99-1.66, P = 0.064). The effect of genotype was similar for treatment with abiraterone or enzalutamide with a negative test for interaction for TTPP (P = 0.997) and TTP (P = 0.749). Multivariable analysis did not show a significant association between genotype and TTP or TTPP. CONCLUSIONS: The HSD3B1 (CC) genotype was associated with shorter TTP and lower PSA response rate in patients with mCRPC treated with abiraterone or enzalutamide. However, the CC genotype did not provide prognostic information beyond that conferred by standard clinical variables, suggesting that it may not be a suitable stand-alone biomarker in mCRPC.

Clinical Management of Cutaneous Adverse Events in Patients on Chemotherapy: A National Consensus Statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology. / Manejo clínico de los eventos adversos cutáneos en pacientes tratados con quimioterapia: consenso nacional de la Academia Española de Dermatología y Venereología y de la Sociedad Española de Oncología Médica.

Although the arrival of new chemotherapy drugs and combinations has brought progress in terms of cancer patient survival, they entail many adverse effects that can compromise treatment, and hence prognosis, of the disease. Cytostatic agents can cause dermatological toxicity, among other side effects. The most familiar adverse effect of chemotherapy is alopecia. Although not serious, this changes the outward appearance of cancer patients. Other adverse effects include hypersensitivity and photosensitivity reactions, hand-foot syndrome, epidermal necrolysis, recall reactions, scleroderma-like reactions, Raynaud's phenomenon, eccrine squamous syringometaplasia, neutrophilic eccrine hidradenitis, nail abnormalities, pigmentation changes and extravasation injuries. Onset of these adverse effects often causes dose reduction and/or delayed treatment, which can affect patient survival and quality of life. It is therefore important to prevent their occurrence and treat them promptly, which requires cooperation between medical oncologists and dermatologists. This article reviews chemotherapy-associated dermatological toxicity, along with its diagnosis and therapeutic management.

Clinical management of cutaneous adverse events in patients on targeted anticancer therapies and immunotherapies: a national consensus statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology.

Progress in the understanding of many tumors has enabled the development of new therapies, such as those targeted at specific molecules involved in cell growth (targeted therapies) or intended to modulate the immune system (immunotherapy). However, along with the clinical benefit provided by these new treatments, new adverse effects have also appeared. Dermatological toxicities such as papulopustular eruptions, xerosis, and pruritus are common with EGFR inhibitors. Other adverse effects have also been described with PDGFR, BCR-ABL, and MAPK tyrosine kinase inhibitors, antiangiogenic drugs, and inhibitors at immune checkpoints such as CTLA-4 and PD-1/PD-L1. Onset of these adverse effects often causes dose reductions and/or delays in administering the prescribed therapy, which can affect patient survival and quality of life. It is, therefore, important to prevent the occurrence of these adverse effects, or to treat unavoidable ones as soon as possible. This requires cooperation between medical oncologists and dermatologists. This article reviews the various dermatological toxicities associated with targeted therapies and immunotherapies, along with their diagnosis and therapeutic management.

An immunohistochemical study of cytokeratins distribution of the human adult male and female urethra.

Surgical treatment of diseases affecting long urethral areas represents a challenge in urology. Recent developments of tissue-engineered urethral substitutes represent a hope for patients. However finding an ideal tissue source for urethral reconstruction first requires proper understanding of the native human urethra physiology and a deep knowledge of the histological and molecular features of the native human urethra. Here we present a comprehensive characterization of male and female urethra by histological, histochemical and immunohistochemical methods with a panel of 15 antibodies. The results demonstrated that the histology of the male and female urethra depend on the area where the sample is taken along its length. Proximal areas of male and female urethra have differential expression of the epithelial basal and suprabasal layer markers CK14 and CK10 which distinguished the prostatic/membranous and proximal female urethra from the bulbar/penile and distal female areas of the urethra. The distal male (penile) and female may be further divided by the distinct expression pattern of CK19. On the other hand, the expression of CK5/6 and CK19 also make a distinction of the proximal and distal female urethra. These results should facilitate a more informed selection of donor graft tissues for urethral replacement. Besides, novel bioengineered urethral tissue approaches should take into account the characterization of the different areas of the urethra presented in this work.

Performance of the clinical index of stable febrile neutropenia (CISNE) in different types of infections and tumors.

PURPOSE: The clinical index of stable febrile neutropenia (CISNE) can contribute to patient safety without increasing the complexity of decision-making. However, febrile neutropenia (FN) is a diverse syndrome. The aim of this analysis is to assess the performance of CISNE according to the type of tumor and infection and to characterize these patients. METHODS: We prospectively recruited 1383 FN episodes in situations of apparent clinical stability. Bonferroni-adjusted z tests of proportions were used to assess the association between the infections suspected at the time of onset and the type of tumor with the risk of serious complications and mortality. The performance of CISNE was appraised in each category using the Breslow-Day test for homogeneity of odds ratios and Forest Plots. RESULTS: 171 patients had a serious complication (12.3 %, 95 % confidence interval 10.7-14.2 %). The most common initial assumptive diagnoses were: fever without focus (34.5 %), upper respiratory infection (14.9 %), enteritis (12.7 %), stomatitis (11.8 %), and acute bronchitis (10.7 %). Lung and breast were the most common tumors, accounting for approximately 56 % of the series. The distribution of complications, mortality, and bacteremia varies for each of these categories. However, Breslow-Day tests indicate homogeneity of the odds ratio of the dichotomized CISNE score to predict complications in all infection and tumor subtypes. CONCLUSION: Despite FN's clinical and microbiological heterogeneity, the CISNE score was seen to be consistent and robust in spite of these variations. Hence, it appears to be a safe tool in seemingly stable FN.

Ethical considerations in presymptomatic diagnosis of autosomal dominant spinocerebellar ataxias. / Consideraciones éticas en el diagnóstico presintomático de ataxias espinocerebelosas autosómico dominantes.

INTRODUCTION: Information on achieving presymptomatic diagnosis of spinocerebellar ataxia (SCA) is limited. The advent of molecular diagnosis makes it possible to identify the carriers of different diseases and has also introduced the prospect of detecting diseases even before their onset. This has drawn attention to the ethical implications that must be considered in these subjects with a view to preserving their physical and psychological well-being. DEVELOPMENT: SCA is composed of a group of neurodegenerative disorders with autosomal dominant inheritance. Only a few publications have described the genetic counselling processes and guidelines to be followed during the process of presymptomatic diagnosis (PSD). The size of the multidisciplinary teams, their areas of expertise, and the number of counselling sessions are different for each of the studies analysed here. However, the basis of presymptomatic diagnosis originates in common guidelines to which members of our team have contributed recently. CONCLUSION: Presymptomatic diagnosis should be performed according to guidelines that safeguard the subjects' welfare. The diagnostic process is only recommended for patients over 18 years old with symptoms suggesting SCA, and a minimum risk of 50%. Genetic counselling programmes must be available in all centres that offer presymptomatic diagnosis of SCA.

[Left ventricular mass, forced baseline spirometry and adipocytokine profiles in obese children with and without metabolic syndrome]. / Masa ventricular izquierda, espirometría basal forzada y perfil de adipocitocinas en niños obesos con y sin síndrome metabólico.

INTRODUCTION: Recent reports have shown an increase in changes in cardiac and pulmonary function among obese patients. Furthermore, it has also been demonstrated that obesity is a state of chronic inflammation. We hypothesized that obese children with metabolic syndrome exhibit a higher percentage of left ventricular hypertrophy and altered spirometry values due to higher levels of inflammation. PATIENTS AND METHODS: Left ventricular mass was studied using echocardiography, baseline forced spirometry by spirometer (FlowScreen) and adipocytokine profiles (adiponectin, IL-6, leptin, MCP-1, PCR-Hs, RBP-4, TNF-( and visfatin) were evaluated in peripubertal obese children with and without metabolic syndrome. RESULTS: Forty-one patients (20 girls and 21 boys) were included in the study, 20 of whom (10 boys and 10 girls) were subjects with metabolic syndrome. Of the adipocytokines studied, only leptin, hs-CRP, MCP-1, and the leptin/adiponectin ratio yielded values that were substantially greater in the group with metabolic syndrome (P<.01). An analysis of left ventricular mass index and baseline spirometry showed no differences between the groups studied. However, of the entire cohort, 9.5% had left ventricular hypertrophy. No significant relationship was found between anthropometric data and adipocytokines and the parameters used to study left ventricular mass and spirometry values on the other. CONCLUSION: At the time the study was performed, left ventricular mass and baseline forced spirometry did not appear to be influenced by inflammatory mechanisms.

Optimization of combined microwave-hot air roasting of malt based on energy consumption and neo-formed contaminants content.

UNLABELLED: To produce specialty malt, malts were roasted by combined microwave-hot air at various specific microwave powers (SP = 2.5 to 3 W/g), microwave heating times (t(mw) = 3.3 to 3.5 min), oven temperatures (T(oven) = 180 to 220 degrees C), and oven heating times (t(oven) = 60 to 150 min). The response variables, color, energy consumption by microwave (E(mw)) and oven (E(oven)), total energy consumption (E(tot)), quantity of neo-formed contaminants (NFCs), which include hydroxymethylfurfural, furfural, furan, and acrylamide were determined. Response surface methodology (RSM) was performed to analyze and predict the optimum conditions for the specialty malt. Production using combined microwave-hot air roasting process based on minimum energy consumption and level of NFCs. At 95% confident level, SP, T(oven), and t(oven) were the most influencing effects with regard to E(tot), whereas t(mw) did not affect E(tot). T(oven) and t(oven) significantly affected malt color. Only T(oven) significantly influenced the NFCs content. The optimum parameters were: SP = 2.68 W/g for 3.44 min, T(oven) = 206 degrees C for 136 min for coffee malt, SP = 2.5 W/g for 3.48 min, T(oven) = 214 degrees C for 136 min for chocolate malt, and SP = 2.5 W/g for 3.48 min, T(oven) = 211 degrees C for 150 min for black malt. Comparing with conventional process, combined microwave-hot air reduced E(tot) by approximately 40%, 26%, and 26% for coffee, chocolate, and black malts, respectively, and reduced HMF, furfural, furan, and acrylamide contents by 40%, 18%, 23%, and 95%, respectively, for black malt. PRACTICAL APPLICATION: An important goal for research institutions and the brewery industry is to produce colored malt by combining microwave and hot air roasting, while saving energy, getting desirable color, and avoiding the formation of carcinogenic and toxic neo-formed contaminants (NFCs). Therefore, one objective of this study was to compare energy consumption and content of NFCs during roasting of malt by hot air-only and combined microwave-hot air processes as well as to determine the effect of specific power, microwave processing time, oven temperature, and oven processing time during combined microwave-hot air roasting. Another objective was to predict the optimum conditions for the production of coffee, chocolate, and black malts.

The health and technological implications of a better control of neoformed contaminants by the food industry.

The recent discovery of the presence of variable amounts of the carcinogenic compound acrylamide in a wide range of severely heat-treated food products, such as fried potatoes, biscuits, bread and coffee or malt, as a result of the heat process, has induced an important research in the area of the Maillard reaction in food. The interaction between a specific food composition and the heat process applied results in the development of complex oxidation and glycation reactions, which give rise to a mixture of flavoured compounds and possible neoformed contaminants (NFC). Recommendations by the European Commission aim at monitoring the content of major NFC, such as acrylamide and furan, in a list of food products commercialized in Europe. On the other hand, the Commission for European Normalization (CEN) has created recently a new workgroup (WG13) responsible for normalization of analytical method for NFC assessment. The European collective research ICARE was carried out to identify the possible health consequences of the ingestion of heat-treated products, characterize the reaction kinetics leading to NFC and evaluate some mitigation procedures proposed by the CIAA toolbox, and finally develop a simple, rapid and non destructive control method based on fluorescence acquisition on the crushed food products and chemometric analysis of the spectral information. This paper summarizes the objectives and essential results obtained in the scope of the project, highlighting the need for evaluating the distribution of NFC in food products commercialized in Europe, as well as the impact of the food formula/recipe and process on Maillard derived NFC food levels. The potential of the Fluoralys sensor regarding its ability to control food contamination with NFC is presented. A decrease in NFC concentration of heat processed food should allow significantly limiting the exposure of populations to NFC and consequently the potential related health risk.

Strategy for the study of the health impact of dietary Maillard products in clinical studies: the example of the ICARE clinical study on healthy adults.

The study of the health impact of dietary Maillard products (MPs) in realistic clinical studies requires the design of nutritionally equivalent diets with high and low levels of MPs. This difficult challenge may be achieved by setting the high-MP diet at the regular daily level, where the common use of grilling, frying, and roasting processes allows significant amounts of carboxymethyllysine, hydroxymethylfurfural and acrylamide to be formed. In such conditions, we show that major lipid degradation does not occur, nor does degradation of vitamin E or thiamine. Based on this finding, the low-MP diet; must be constructed accordingly, by replacing all high-temperature techniques with steam cooking or the absence of cooking. The cooking fat must be replaced with similar raw fat as seasoning in the low-MP diet, the high caloric density resulting from water loss in the high-MP diet must be compensated by higher food quantities offered in the low-MP diet, and the vitamin loss in fruit and vegetables resulting from high temperatures in the high-MP diet can be circumvented by increasing the corresponding portion size. In the ICARE study, equilibrated diets were proposed, fulfilling all nutritional needs, but with a 3- to 45-fold difference in MP concentrations. Individual quantification of nutritional and MP intakes will ensure the nutritional equivalence of the two diets and allow for quantification of the specific impact of ingested MPs.

Potential of front face fluorescence associated to PLS regression to predict nutritional parameters in heat treated infant formula models.

This work shows that front face fluorescence spectroscopy associated to partial least squares (PLS) calibration is a fast and simple method to assess the nutritional impact of heat treatment on milk samples. Emission spectra of tryptophan (Trp) and of advanced Maillard products (AMP) were recorded on intact milk samples non-heated and heated at seven temperatures (72 degrees C, 80 degrees C, 87 degrees C, 95 degrees C, 100 degrees C, 110 degrees C and 115 degrees C) for six different times (from 2 min to 9.5 min) by means of front face fluorescence. PLS calibrations were constructed in order to indirectly quantify three indicators: vitamin C, protein denaturation and accumulation of Maillard products using the fluorescence of advanced Maillard products and soluble tryptophan method (FAST). The prediction models allowed obtaining an estimation of these indicators with a relative error of 12% for vitamin C and about 18% for the FAST index and soluble whey protein ratio.

Evaluation of the maillard reaction in infant formulas by means of front-face fluorescence.

Foods are complex mixtures of macro- and micronutrients, which interact, leading to oxidation, glycation, and hydrolysis upon heating (e.g., sterilization, cooking) and storage. Their nutritional quality and safety are consequently affected, justifying the need for accurate monitoring of the evolution of the food composition during processing and shelf life. Classical chromatographic analysis as well as newly proposed rapid methods based on fluorescence spectrometry analyses were applied on whey powder-based models and commercial samples (in powdered form and ultrahigh temperature [UHT] sterilized), some of which had been previously submitted to protein hydrolysis. These samples were incubated for 48 h at 60 degrees C to mimic accelerated storage. Fluorescence fingerprints addressing modifications in the product composition during processing were recorded and analyzed by chemometric methods. Carboxymethyllysine (Nepsilon-[carboxymethyl]lysine; CML) was measured using an ELISA method. Fluorescence, recorded in a front-face mode on intact samples, is very sensitive to pertinent physicochemical changes induced by heat treatment, formulation (the moisture level in powders, presence of vitamin C and iron), and storage. Similar trends were observed between powders' fluorescence and CML-for example, a strong effect of protein hydrolysis and increasing water content. Addition of vitamin C was associated with an antioxidant effect despite the presence of iron. Good calibration models were obtained for predicting CML from fluorescence spectra both in food models and in commercial samples, although more work is needed to obtain accurate and robust calibration models. Results show the potential of nondestructively applied fluorescence spectrometry for measuring CML in formulas, a rapid, simple, and cost-effective method to monitor formula quality.

Effects of sterilization, packaging, and storage on vitamin C degradation, protein denaturation, and glycation in fortified milks.

Monitoring the nutritional quality of dietetic milk throughout its shelf life is particularly important due to the high susceptibility of some vitamins to oxidation, and the continuous development of the Maillard reaction during storage. The objective of this paper was to evaluate the vitamin C content and protein modification by denaturation and glycation on fortified milk samples (growth milks) destined for 1- to 3-yr-old children. The influences of the sterilization process, formulation, packaging, and storage duration at ambient temperature in the dark were studied. Vitamin C degradation was particularly influenced by type of packaging. The use of a 3-layered opaque bottle was associated with complete oxidation of vitamin C after 1 mo of storage, whereas in the 6-layered opaque bottle, which has an oxygen barrier, the vitamin C content slowly decreased to reach 25% of the initial concentration after 4 mo of storage. However, no significant effect of vitamin C degradation during storage could be observed in terms of Maillard reaction, despite the fact that a probable impact occurred during sterilization. Furosine content and the FAST (fluorescence of advanced Maillard products and soluble tryptophan) index-indicators of the early and advanced Maillard reaction, respectively-were significantly higher in the in-bottle sterilized milk samples compared with UHT samples, and in fortified milk samples compared with cow milk. However, after 1 mo, the impact of storage was predominant, increasing the furosine level and the FAST index at similar levels for the differently processed samples. The early Maillard reaction developed continuously throughout the storage period.In conclusion, only packaging comprising an oxygen and light barrier is compatible with vitamin C fortification of milk. Furthermore, short storage time or low storage temperature is needed to retard vitamin C degradation, protein denaturation, and development of the Maillard reaction.

Antioxidant vitamins and degenerative pathologies. A review of vitamin C.

In this review we describe how tissues are protected against free radicals and we detail the mechanisms by which the insufficient reduction of ascorbate is involved in glycation and oxidation processes on proteins.

The fluorescence of advanced Maillard products is a good indicator of lysine damage during the Maillard reaction.

The objective of this study was to determine whether in heat-treated milk-resembling models or milk there is a lag phase, before lactulosyllysine (LL) is converted into advanced Maillard products (AMP), and if there is a step during the heat treatment where LL is actively degraded into AMP. For that purpose, a low temperature (60-85 degrees C) and a long heat treatment (15-90 h) were chosen. We observe that the heat treatment first induces a parallel increase in furosine and AMP fluorescence, confirming that AMP are produced very early during the heat treatment. At this step, both indicators are correlated with each other and precisely reflect the lysine damage. After a time, however, furosine reaches a steady-state concentration, whereas AMP fluorescence still increases, remaining correlated with the lysine blockage. Nevertheless, heat treatment applied to milk does not reach this step so that AMP fluorescence appears as a rapid alternative to furosine quantification.

The FAST method, a rapid approach of the nutritional quality of heat-treated foods.

The FAST method is based on the determination of maximal fluorescence emission when exciting at 330-350 nm, which corresponds to molecular structures formed between reducing sugars or oxidizing lipids and lysine residues of proteins. This fluorescence is dependent on heat treatment and related to protein nutritional loss. Applied to a soluble extract of the food and corrected for the protein concentration of the solution obtained, using Trp fluorescence, the method allows to calculate the FAST index (FI), an indicator of the nutritional damage during heat process. The method, firstly validated on milk samples, is demonstrated here to well correlate with lysine damage on various food products, such as heat-treated milk and breakfast cereals, essentially modified by the Maillard reaction, and roasted soybean or cooked salmon, where interactions between oxidizing lipids and proteins better take place. Independently on the food product or the type of heat process, the FAST index appears always well correlated (r2: 0.84-0.98) to the lysine loss, the latter being estimated by determination of acid-released lysine, fluorescamine-reactive lysine or infrared. Shortly, roasted corn flakes appeared to be more damaged than extrudated flour (FI 100 and lysine blockage 40% instead of 55 and 30%), condensed milk more than UHT milk (FI 150 and 85% of acid-released lysine instead of 80 and 94%), and steam-cooked salmon much less than pan-fried (FI 28 instead of 372). Roasted soy can reach FI of more than 300 corresponding to chemical lysine loss of 40% and poultry-digestive lysine loss of 100%. As a conclusion, the FAST method, once precisely calibrated with pertinent nutritional indicators, should be of great interest for controlling or adapting a process in order to ensure a better nutritional quality for the food product.

Serine/threonine protein phosphatase 5 (PP5) participates in the regulation of glucocorticoid receptor nucleocytoplasmic shuttling.

BACKGROUND: In most cells glucocorticoid receptors (GR) reside predominantly in the cytoplasm. Upon hormone binding, the GR translocates into the nucleus, where the hormone-activated GR-complex regulates the transcription of GR-responsive genes. Serine/threonine protein phosphatase type 5 (PP5) associates with the GR-heat-shock protein-90 complex, and the suppression of PP5 expression with ISIS 15534 stimulates the activity of GR-responsive reporter plasmids, without affecting the binding of hormone to the GR. RESULTS: To further characterize the mechanism by which PP5 affects GR-induced gene expression, we employed immunofluorescence microscopy to track the movement of a GR-green fluorescent fusion protein (GR-GFP) that retained hormone binding, nuclear translocation activity and specific DNA binding activity, but is incapable of transactivation. In the absence of glucocorticoids, GR-GFP localized mainly in the cytoplasm. Treatment with dexamethasone results in the efficient translocation of GR-GFPs into the nucleus. The nuclear accumulation of GR-GFP, without the addition of glucocorticoids, was also observed when the expression of PP5 was suppressed by treatment with ISIS 15534. In contrast, ISIS 15534 treatment had no apparent effect on calcium induced nuclear translocation of NFAT-GFP. CONCLUSION: These studies suggest that PP5 participates in the regulation of glucocorticoid receptor nucleocytoplasmic shuttling, and that the GR-induced transcriptional activity observed when the expression of PP5 is suppressed by treatment with ISIS 15534 results from the nuclear accumulation of GR in a form that is capable of binding DNA yet still requires agonist to elicit maximal transcriptional activation.

Identification of an estrogen-inducible phosphatase (PP5) that converts MCF-7 human breast carcinoma cells into an estrogen-independent phenotype when expressed constitutively.

The proliferation of many estrogen receptor (ER)-positive breast cancer cells depends on estradiol, and tumors arising from these cells are often responsive initially to treatment with selective ER modulators, which produce an antiestrogen effect. However, tumors that are refractory to the antiestrogenic effects of selective ER modulators often reemerge, and the prognosis for these patients is poor because of the lack of additional effective therapy. Accordingly, deciphering the cellular events associated with estrogen-dependent growth and the subsequent outgrowth of tumors with an estrogen-independent phenotype is of considerable interest. Here we show that the expression of PP5, an evolutionarily conserved Ser/Thr phosphatase that functions as an inhibitor of glucocorticoid- and p53-induced signaling cascades leading to growth suppression, is responsive to 17beta-estradiol (E(2)) in ER-positive human breast carcinoma cells (MCF-7). Northern analysis revealed that E(2)-induced PP5 expression is blocked by treatment with tamoxifen, and a consensus ER recognition element was identified in the PP5 promoter. The PP5-ER recognition element associates with human ERs and confers E(2)-induced transcriptional activation to reporter plasmids. The specific inhibition of PP5 expression ablates E(2)-mediated proliferation in MCF-7 cells without having an apparent effect on E(2)-induced expression of c-myc or cyclin D1. Thus, although critical for cell growth, PP5 likely acts either downstream or independently of c-Myc and Cyclin D1. To further characterize the role of PP5 in E(2)-regulated growth control, we constructed stable MCF-7 cell lines in which the expression of PP5 was placed under the control of tetracycline-regulated transactivator and operator plasmids. Studies with these cells revealed that the constitutive overexpression of PP5 affords E(2)-dependent MCF-7 cells with the ability to proliferate in E(2)-depleted media. Together, these studies indicate that E(2)-induced PP5 expression functions to enhance E(2)-initiated signaling cascades leading to cell division and that aberrant PP5 expression may contribute to the development of MCF-7 cells with an estrogen-independent phenotype.