Mechanistic Association of Hepatoblastoma with Cerebral Palsy: A Narrative Review.

Hepatoblastoma is a rare liver cancer that occurs most often in children who present with lower birth weight. Cerebral palsy (CP) is a neurodevelopmental disorder distinguished by irregularities in muscle tone, movement, and motor skills. CP is caused by damage to the developing brain and is often associated with secondary complications such as severe constipation. Clinicians must be aware of sudden worsening constipation occurring in CP children because it can also be a sign of hepatoblastoma. The aim of this review is to summarize the current understanding of the risks for hepatoblastoma development in children with CP. Cancer risks likely include dysfunction of the immune system surveillance in CP children. Elevated C-reactive protein and tumor necrosis factor-alpha levels may be higher in children with CP, which weakens their innate immune system. Metabolic disruption increases the risk of some cancers, and poor nutrition and reduced growth that occur in CP patients may have an impact on cancer development through a loss in immune function. Increased mobility and physical activity can increase the T-cell, natural killer cell, and neutrophil population. Children with CP tend to engage poorly in physical activity, and consequently, their immune system is affected. There are multiple factors associated with CP that increase the risk of childhood cancers such as hepatoblastoma.

Estrogen-induced signalling and the renal contribution to salt and water homeostasis.

The kidney is considered to be one of the most estrogen-responsive, not reproductive organs in the body. Different estrogen receptors (ERs) show sex-specific differences in expression along the nephron and the expression of different ERs also changes with the estrous cycle of the female. The kidney becomes more estrogen-sensitive when estradiol levels are at their highest, just prior to ovulation. This review discusses the different mechanisms by which estradiol can modify the salt and water conservation processes of the kidney through transporter regulation to support the fluid and electrolyte homeostasis changes required in mammalian reproduction. The kidney plays a critical role in regulating blood pressure by controlling fluid homeostasis, and so protects the female cardiovascular system from dramatic changes in whole body fluid volume that occur at critical points in the human menstrual cycle and in pregnancy. This is augmented by the direct actions of estradiol on the cardiovascular system, for example through the direct stimulation of endothelial nitric oxide (NO) synthase, which releases NO to promote vasodilation. This and other mechanisms are less evident in the male and give women a degree of cardiovascular protection up until menopause, when the risks of cardiovascular disease and chronic kidney disease begin to match the risks experienced by males.

Oestrogen actions contribute to female gender-specific risks in the development of lung carcinoma.

Lung cancer is increasing in incidence particularly among women, associated with a global change in smoking habits. Steroid hormones, particularly oestrogen exert an influence on tumour progression in tissues where their target receptor is expressed. Oestrogen receptor, particularly ERß is highly expressed in the lung and becomes more highly expressed in lung carcinogenesis. Genes involved in the process of lung carcinoma progression and signalling cascades linked to invasion and angiogenesis are modulated by oestrogen receptors. This review intends to collate recently published evidence identifying a role for oestrogen in the initiation and progression of lung carcinoma and how these two processes are differentially affected by circulating oestrogens both in women and in men. Circulating oestrogens may be a significant risk factor in women's susceptibility to lung carcinoma and also provide an additional approach for more targeted therapy.

Lavender essential oil induces oxidative stress which modifies the bacterial membrane permeability of carbapenemase producing Klebsiella pneumoniae.

Misuse of antibiotics in the clinical and agricultural sectors has caused the emergence of multidrug-resistant (MDR) Klebsiella pneumoniae which contributes a threat to human health. In this study, we assessed the feasibility of lavender essential oil (LVO) as an antimicrobial agent in combinatory therapy with meropenem in suppressing the growth of carbapenemase-producing K. pneumoniae (KPC-KP). Synergistic interactions between LVO and meropenem were detected, which significantly reduce the inhibitory concentration of both LVO and meropenem by 15 and 4-fold respectively. Comparative proteomic profiling identified a disruption in the bacterial membrane via oxidative stress that was indicated by loss of membrane and cytoplasmic proteins and the upregulation of oxidative regulators. As a proof of concept, zeta potential measurements showed a change in cell surface charge while outer membrane permeability measurement indicated an increase in membrane permeability following exposure to LVO. This was indicative of a disrupted outer membrane. Ethidium bromide influx/efflux assays demonstrated no significant efflux pump inhibition by LVO, and scanning electron microscopy revealed irregularities on the cell surface after exposure to LVO. Oxidative stress was also detected with increased level of ROS and lipid peroxidation in LVO-treated cells. In conclusion, our data suggest that LVO induced oxidative stress in K. pneumoniae which oxidizes the outer membrane, enabling the influx of generated ROS, LVO and meropenem into the bacterial cells, causing damage to the cells and eventually death.

Virotherapy: Current Trends and Future Prospects for Treatment of Colon and Rectal Malignancies.

Colorectal cancer (CRC) is one of the most common malignancies. In recent decades, early diagnosis and conventional therapies have resulted in a significant reduction in mortality. However, late stage metastatic disease still has very limited effective treatment options. There is a growing interest in using viruses to help target therapies to tumour sites. In recent years the evolution of immunotherapy has emphasised the importance of directing the immune system to eliminate tumour cells; we aim to give a state-of-the-art over-view of the diverse viruses that have been investigated as potential oncolytic agents for the treatment of CRC.

Disruption of KPC-producing Klebsiella pneumoniae membrane via induction of oxidative stress by cinnamon bark (Cinnamomum verum J. Presl) essential oil.

Klebsiella pneumoniae (KP) remains the most prevalent nosocomial pathogen and carries the carbapenemase (KPC) gene which confers resistance towards carbapenem. Thus, it is necessary to discover novel antimicrobials to address the issue of antimicrobial resistance in such pathogens. Natural products such as essential oils are a promising source due to their complex composition. Essential oils have been shown to be effective against pathogens, but the overall mechanisms have yet to be fully explained. Understanding the molecular mechanisms of essential oil towards KPC-KP cells would provide a deeper understanding of their potential use in clinical settings. Therefore, we aimed to investigate the mode of action of essential oil against KPC-KP cells from a proteomic perspective by comparing the overall proteome profile of KPC-KP cells treated with cinnamon bark (Cinnamomum verum J. Presl) essential oil (CBO) at their sub-inhibitory concentration of 0.08% (v/v). A total of 384 proteins were successfully identified from the non-treated cells, whereas only 242 proteins were identified from the CBO-treated cells. Proteins were then categorized based on their biological processes, cellular components and molecular function prior to pathway analysis. Pathway analysis showed that CBO induced oxidative stress in the KPC-KP cells as indicated by the abundance of oxidative stress regulator proteins such as glycyl radical cofactor, catalase peroxidase and DNA mismatch repair protein. Oxidative stress is likely to oxidize and disrupt the bacterial membrane as shown by the loss of major membrane proteins. Several genes selected for qRT-PCR analysis validated the proteomic profile and were congruent with the proteomic abundance profiles. In conclusion, KPC-KP cells exposed to CBO undergo oxidative stress that eventually disrupts the bacterial membrane possibly via interaction with the phospholipid bilayer. Interestingly, several pathways involved in the bacterial membrane repair system were also affected by oxidative stress, contributing to the loss of cells viability.

A novel role for estrogen-induced signaling in the colorectal cancer gender bias.

Colorectal cancer (CRC) is a malignancy whose incidence is increasing globally, and there is a gender difference in the increasing risk. Evidence from hormone replacement therapy studies points to a role for circulating estrogens in suppressing the development of CRC. Estrogen receptor-ß has been identified as a tumor suppressor, but other actions of estrogen may also contribute to the difference in CRC incidence between men and women. The KCNQ1/KCNE3 potassium channel is regulated by estrogen in order to modulate chloride secretion during the menstrual cycle; the effect of estrogen on the colon is to promote fluid conservation during the implantation window. KCNQ1 is also a tumor suppressor in CRC, and its sustained expression has been linked to suppression of the Wnt/ß-catenin signaling pathway that contributes to CRC tumor progression. KCNQ1 regulation may represent a link between the normal physiological actions of estrogen in the colon and the hormone's apparent tumor-suppressive effects in CRC development.

GPER mediates differential effects of estrogen on colon cancer cell proliferation and migration under normoxic and hypoxic conditions.

The estrogen receptor ERß is the predominant ER subtype expressed in normal well-differentiated colonic epithelium. However, ERß expression is lost under the hypoxic microenvironment as colorectal cancer (CRC) malignancy progresses. This raises questions about the role of signalling through other estrogen receptors such as ERα or G-protein coupled estrogen receptor (GPER, GPR30) by the estrogen 17ß-estradiol (E2) under hypoxic conditions after ERß is lost in CRC progression. We tested the hypothesis that E2 or hypoxia can act via GPER to contribute to the altered phenotype of CRC cells. GPER expression was found to be up-regulated by hypoxia and E2 in a panel of CRC cell lines. The E2-modulated gene, Ataxia telangiectasia mutated (ATM), was repressed in hypoxia via GPER signalling. E2 treatment enhanced hypoxia-induced expression of HIF1-α and VEGFA, but repressed HIF1-α and VEGFA expression under normoxic conditions. The expression and repression of VEGFA by E2 were mediated by a GPER-dependent mechanism. E2 treatment potentiated hypoxia-induced CRC cell migration and proliferation, whereas in normoxia, cell migration and proliferation were suppressed by E2 treatment. The effects of E2 on these cellular responses in normoxia and hypoxia were mediated by GPER. In a cohort of 566 CRC patient tumor samples, GPER expression significantly associated with poor survival in CRC Stages 3-4 females but not in the stage-matched male population. Our findings support a potentially pro-tumorigenic role for E2 in ERß-negative CRC under hypoxic conditions transduced via GPER and suggest a novel route of therapeutic intervention through GPER antagonism.

Bidirectional KCNQ1:ß-catenin interaction drives colorectal cancer cell differentiation.

The K+ channel KCNQ1 has been proposed as a tumor suppressor in colorectal cancer (CRC). We investigated the molecular mechanisms regulating KCNQ1:ß-catenin bidirectional interactions and their effects on CRC differentiation, proliferation, and invasion. Molecular and pharmacologic approaches were used to determine the influence of KCNQ1 expression on the Wnt/ß-catenin signaling and epithelial-to-mesenchymal transition (EMT) in human CRC cell lines of varying stages of differentiation. The expression of KCNQ1 was lost with increasing mesenchymal phenotype in poorly differentiated CRC cell lines as a consequence of repression of the KCNQ1 promoter by ß-catenin:T-cell factor (TCF)-4. In well-differentiated epithelial CRC cell lines, KCNQ1 was localized to the plasma membrane in a complex with ß-catenin and E-cadherin. The colocalization of KCNQ1 with adherens junction proteins was lost with increasing EMT phenotype. ShRNA knock-down of KCNQ1 caused a relocalization of ß-catenin from the plasma membrane and a loss of epithelial phenotype in CRC spheroids. Overexpression of KCNQ1 trapped ß-catenin at the plasma membrane, induced a patent lumen in CRC spheroids, and slowed CRC cell invasion. The KCNQ1 ion channel inhibitor chromanol 293B caused membrane depolarization, redistribution of ß-catenin into the cytosol, and a reduced transepithelial electrical resistance, and stimulated CRC cell proliferation. Analysis of human primary CRC tumor patient databases showed a positive correlation between KCNQ1:KCNE3 channel complex expression and disease-free survival. We conclude that the KCNQ1 ion channel is a target gene and regulator of the Wnt/ß-catenin pathway, and its repression leads to CRC cell proliferation, EMT, and tumorigenesis.

Tamoxifen Suppresses the Growth of Malignant Pleural Mesothelioma Cells.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare but highly aggressive malignancy most often associated with exposure to asbestos. Recent evidence points to oestrogen receptor (ER)-ß having a tumour-suppressor role in MPM progression, and this raises the question of whether selective modulators of ERs could play a role in augmenting MPM therapy. MATERIALS AND METHODS: We investigated the action of tamoxifen in inhibiting the growth and modulating the cisplatin sensitivity of four MPM cell lines. RESULTS: Tamoxifen inhibited the growth of MPM cells and also modulated their sensitivity to cisplatin. The MPM cell lines expressed ERß, but the actions of tamoxifen were not blocked by antagonism of nuclear ERs. Tamoxifen treatment repressed the expression of cyclins by MPM cells, resulting in cell-cycle arrest and caspase-3-coupled apoptosis signaling. CONCLUSION: The ER-independent actions of tamoxifen on MPM cell proliferation and cell-cycle progression may have clinical benefits for a subset of patients with MPM.

Renin-Angiotensin-Aldosterone System Antagonism and Polycystic Kidney Disease Progression.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disease characterised by the formation of multiple renal cysts that adversely affect renal function. ADPKD shows significant progression with age when complications due to hypertension are most significant. The activation of the renin-angiotensin-aldosterone system (RAAS) occurs in progressive kidney disease leading to hypertension. The RAAS system may also contribute to ADPKD progression by stimulating signalling pathways in the renal cyst cells to promote growth and deregulate epithelial transport. This mini review focuses on the contribution of the RAAS system to renal cyst enlargement and the potential for antagonists of the RAAS system to suppress cyst enlargement as well as control ADPKD-associated hypertension.

Physiological techniques in the study of rapid aldosterone effects.

Molecular imaging and electrophysiological techniques are powerful tools to analyze the responses stimulated by aldosterone and other hormones in target tissues. Studies with Ussing-type chambers can be used to measure and characterize changes in transepithelial currents resulting from hormone treatment. Confocal imaging techniques can be used in real time or in fixed preparations to evaluate the localization of receptors, signalling intermediates, and transporters.

Estrogen increases ENaC activity via PKCδ signaling in renal cortical collecting duct cells.

The most active estrogen, 17ß-estradiol (E2), has previously been shown to stimulate a female sex-specific antisecretory response in the intestine. This effect is thought to contribute to the increase in whole body extracellular fluid (ECF) volume which occurs in high estrogen states, such as in the implantation window during estrous cycle. The increased ECF volume may be short-circuited by a renal compensation unless estrogen exerts a proabsorptive effect in the nephron. Thus, the effect of E2 on ENaC in kidney cortical collecting duct (CCD) cells is of interest to understand estrogen regulation of ECF volume. Previous studies showed a rapid stimulatory effect of estrogen on ENaC in bronchial epithelium. In this study we examined if such a rapid effect on Na(+) absorption could occur in the kidney. Experiments were carried out on murine M1-CCD cell cultures. E2 (25 nmol/L) treatment caused a rapid-onset (<15 min) and sustained increase in the amiloride-sensitive Na(+) current (INa) in CCD monolayers mounted in Ussing chambers (control, 1.9 ± 0.2 µA/cm(2); E2, 4.7 ± 0.3 µA/cm(2); n = 43, P < 0.001), without affecting the ouabain-sensitive Na(+)/K(+) pump current. The INa response to E2 was inhibited by PKCδ activity antagonism with rottlerin (5 µmol/L), inhibition of matrix metalloproteinases activity with GM6001 (1 µmol/L), inhibition of EGFR activity with AG1478 (10 µmol/L), inhibition of PLC activity with U-73122 (10 µmol/L), and inhibition of estrogen receptors with the general ER antagonist ICI-182780 (100 nmol/L). The estrogen activation of INa could be mimicked by the ERα agonist PPT (1 nmol/L). The nuclear excluded estrogen dendrimer conjugate (EDC) induced similar stimulatory effects on INa comparable to free E2. The end target for E2 stimulation of PKCδ was shown to be an increased abundance of the γ-ENaC subunit in the apical plasma membrane of CCD cells. We have demonstrated a novel rapid "nongenomic" function of estrogen to stimulate ENaC via ERα-EGFR transactivation in kidney CCD cells. We propose that the salt-retaining effect of estrogen in the kidney together with its antisecretory action in the intestine are the molecular mechanisms causing the expanded ECF volume in high-estrogen states.

Malignant pleural mesothelioma incidence and survival in the Republic of Ireland 1994-2009.

OBJECTIVE: Malignant pleural mesothelioma (MPM) is a rare malignancy associated with exposure to asbestos. The protracted latent period of MPM means that its incidence has continued to rise across Europe after the introduction of restrictions on asbestos use. In order to obtain a clearer indication of trends in the Republic of Ireland (ROI), incidence and survival were assessed based on all MPM cases reported since the establishment of the National Cancer Registry of Ireland (NCR). METHODS: NCR recorded 337 MPM diagnoses in the ROI during 1994-2009. Survival was assessed for all cases diagnosed with adequate follow-up (n=330). Crude and European age-standardized incidence rates were calculated for all cases and for 4-year periods. A Cox model of observed (all-cause) survival was used to generate hazard ratios for the effect of: gender; age at diagnosis; diagnosis cohort; region of residence; histological type; and tumour stage. Single P-values for the variables indicated were calculated using either a stratified log-rank test or stratified trend test. RESULTS: Over the study period the age-standardized MPM incidence in the ROI rose from 4.98cases per million (cpm) to 7.24cpm. The 1-year survival rate for all MPM cases was 29.6% (CI 24.7-34.6%). Excess mortality risk was associated with age at diagnosis (75-89 yrs vs. 55-64 yrs, HR 1.88, 95% CI 1.35-2.63, P<0.001) and tumour stage (III vs. I HR 1.57, 95% CI 1.00-2.48, P<0.05; IV vs. I HR 1.55, 95% CI 1.08-2.21, P<0.05). Age showed a significant survival trend (P<0.001) but tumour stage did not (P=0.150). There was significant heterogeneity between the survival of patients resident in different regions (P=0.027). CONCLUSION: MPM incidence and mortality continued to rise in the ROI after the restrictions on asbestos use and the predictors of survival detected in this study are broadly consistent with those identified for other countries.

Rapid aldosterone actions on epithelial sodium channel trafficking and cell proliferation.

Aldosterone regulates blood pressure through its effects on the kidney and the cardiovascular system. Dysregulation of aldosterone signalling can result in hypertension which in turn can lead to chronic pathologies of the kidney such as renal fibrosis and nephropathy. Aldosterone acts by binding to the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues such as segments of the distal nephron including the connecting tubule and cortical collecting duct (CCD). Aldosterone also promotes the activation of protein kinase signalling cascades that are coupled to growth factor receptors and act directly on specific substrates in the cell membrane or cytoplasm. The rapid actions of aldosterone can also modulate gene expression through the phosphorylation of transcription factors. Aldosterone is a key regulator of Na(+) conservation in the distal nephron, largely through multiple mechanisms that modulate the activity of the epithelial Na(+) channel (ENaC). Aldosterone transcriptionally up-regulates the ENaCα subunit and also up regulates serum and glucocorticoid-regulated kinase-1 (SGK1) that indirectly regulates the ubiquitination of ENaC subunits. Aldosterone promotes the activation of protein kinase D1 (PKD1) which can modify the activity of ENaC and other transporters through effects on sub-cellular trafficking. In M1-CCD cells, early sub-cellular trafficking causes the redistribution of ENaC subunits within minutes of treatment with aldosterone. ENaC subunits can also interact directly with phosphatidylinositide signalling intermediates in the membrane and the mechanism by which PKD isoforms regulate protein trafficking is through the control of vesicle fission from the trans Golgi network by activation of phosphatidylinositol 4-kinaseIIIß (PI4KIIIß).

Aldosterone-induced ENaC and basal Na+/K+-ATPase trafficking via protein kinase D1-phosphatidylinositol 4-kinaseIIIß trans Golgi signalling in M1 cortical collecting duct cells.

Aldosterone regulates Na(+) transport in the distal nephron through multiple mechanisms that include the transcriptional control of epithelial sodium channel (ENaC) and Na(+)/K(+)-ATPase subunits. Aldosterone also induces the rapid phosphorylation of Protein Kinase D1 (PKD1). PKD isoforms regulate protein trafficking, by the control of vesicle fission from the trans Golgi network (TGN) through activation of phosphatidylinositol 4-kinaseIIIß (PI4KIIIß). We report rapid ENaCγ translocation to the plasma membrane after 30 min aldosterone treatment in polarized M1 cortical collecting duct cells, which was significantly impaired in PKD1 shRNA-mediated knockdown cells. In PKD1-deficient cells, the ouabain-sensitive current was significantly reduced and Na(+)/K(+)-ATPase α and ß subunits showed aberrant localization. PKD1 and PI4KIIIß localize to the TGN, and aldosterone induced an interaction between PKD1 and PI4KIIIß following aldosterone treatment. This study reveals a novel mechanism for rapid regulation of ENaC and the Na(+)/K(+)-ATPase, via directed trafficking through PKD1-PI4KIIIß signalling at the level of the TGN.

Bruton's tyrosine kinase is required for apoptotic cell uptake via regulating the phosphorylation and localization of calreticulin.

In addition to regulating B cell development and activation, Bruton's tyrosine kinase (Btk) functions downstream of multiple TLRs, including TLR7, to regulate innate immune responses in myeloid cells. Although critical for defense against RNA viruses such as influenza and Sendai virus, recognition of self-RNA by TLR7 also has been shown to be an important contributor to the pathophysiology of systemic lupus erythematosus. To date, the role of Btk in regulating TLR7-mediated responses is poorly understood. In the current study, we have demonstrated a hitherto undiscovered role for Btk in apoptotic cell uptake, identifying the molecular chaperone calreticulin (CRT) as a novel substrate for Btk in regulating this response. CRT together with the transmembrane receptor CD91 function at the cell membrane and regulate uptake of C1q-opsonised apoptotic cells. Our results show that Btk directly phosphorylates CRT and that in the absence of Btk, CRT fails to localize with CD91 at the cell surface and at the phagocytic cup. Critically, a blocking Ab against CRT in wild-type macrophages mimics the inability of Btk-deficient macrophages to phagocytose apoptotic cells efficiently, indicating the critical importance of Btk in regulating CRT-driven apoptotic cell uptake. Our data have revealed a novel regulatory role for Btk in mediating apoptotic cell clearance, with CRT identified as the critical component of the CRT/CD91/C1q system targeted by Btk. Given the importance of clearing apoptotic cell debris to prevent inappropriate exposure of TLRs to endogenous ligands, our results have important implications regarding the role of Btk in myeloid cell function.

Sustained expression of steroid receptor coactivator SRC-2/TIF-2 is associated with better prognosis in malignant pleural mesothelioma.

INTRODUCTION: Estrogen receptor beta (ERß) overexpression by malignant pleural mesothelioma (MPM) tumor cells correlates with enhanced patient survival. ER-regulated transcription is mediated by the p160 family of steroid receptor coactivators (SRCs), and SRC isoform overexpression is associated with worse prognosis in many steroid-related malignancies. The aim of this study was to establish whether SRC isoform expression varied between individual MPM tumors with positive or negative prognostic significance. METHODS: Immunohistochemical analysis of tumor biopsies from 89 subjects with confirmed histological diagnosis of MPM and biopsies from 3 normal control subjects was performed to detect the expression of SRC-1, SRC-2 (TIF-2), SRC-3 (AIB-1), and ERß. Allred scores for expression of ERß and each of the SRCs were determined, and Kaplan-Meier survival curves were calculated to correlate biomarker expression, gender, and histology type with postdiagnosis survival. RESULTS: ERß and all the SRCs were expressed at high levels in normal pleural mesothelium, and expression of each biomarker was reduced or lost in a subset of the MPM subjects; however, postdiagnosis survival only significantly correlated with TIF-2 expression. Low or intermediate expression of TIF-2 correlated with reduced median postdiagnosis survival (9 months) compared with those subjects whose tumors highly expressed TIF-2 (20 months) (p = 0.036, log-rank test). CONCLUSIONS: Maintained high expression of TIF-2 in tumor cells is a positive prognostic indicator for postdiagnosis survival in patients with confirmed MPM. This is the first clinical study to correlate high TIF-2 expression with improved patient prognosis in any malignancy.

Mechanisms underlying rapid aldosterone effects in the kidney.

The steroid hormone aldosterone is a key regulator of electrolyte transport in the kidney and contributes to both homeostatic whole-body electrolyte balance and the development of renal and cardiovascular pathologies. Aldosterone exerts its action principally through the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues. Aldosterone also stimulates the activation of protein kinases and secondary messenger signaling cascades that act independently on specific molecular targets in the cell membrane and also modulate the transcriptional action of aldosterone through MR. This review describes current knowledge regarding the mechanisms and targets of rapid aldosterone action in the nephron and how aldosterone integrates these responses into the regulation of renal physiology.

Estrogen receptor ß exerts tumor repressive functions in human malignant pleural mesothelioma via EGFR inactivation and affects response to gefitinib.

BACKGROUND: The role of estrogen and estrogen receptors in oncogenesis has been investigated in various malignancies. Recently our group identified estrogen receptor beta (ERß) expression as an independent prognostic factor in the progression of human Malignant Pleural Mesothelioma (MMe), but the underlying mechanism by which ERß expression in tumors determines clinical outcome remains largely unknown. This study is aimed at investigating the molecular mechanisms of ERß action in MMe cells and disclosing the potential translational implications of these results. METHODS: We modulated ERß expression in REN and MSTO-211H MMe cell lines and evaluated cell proliferation and EGF receptor (EGFR) activation. RESULTS: Our data indicate that ERß knockdown in ER positive cells confers a more invasive phenotype, increases anchorage independent proliferation and elevates the constitutive activation of EGFR-coupled signal transduction pathways. Conversely, re-expression of ERß in ER negative cells confers a more epithelioid phenotype, decreases their capacity for anchorage independent growth and down-modulates proliferative signal transduction pathways. We identify a physical interaction between ERß, EGFR and caveolin 1 that results in an altered internalization and in a selective reduced activation of EGFR-coupled signaling, when ERß is over-expressed. We also demonstrate that differential expression of ERß influences MMe tumor cell responsiveness to the therapeutic agent: Gefitinib. CONCLUSIONS: This study describes a role for ERß in the modulation of cell proliferation and EGFR activation and provides a rationale to facilitate the targeting of a subgroup of MMe patients who would benefit most from therapy with Gefitinib alone or in combination with Akt inhibitors.