The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.

Endometrial cancer (ECa) is the most common female gynecologic cancer. When comparing the two histological subtypes of endometrial cancer, Type II tumors are biologically more aggressive and have a worse prognosis than Type I tumors. Current treatments for Type II tumors are ineffective, and new targeted therapies are urgently needed. LIFR and its ligand, LIF, have been shown to play a critical role in the progression of multiple solid cancers and therapy resistance. The role of LIF/LIFR in the progression of Type II ECa, on the other hand, is unknown. We investigated the role of LIF/LIFR signaling in Type II ECa and tested the efficacy of EC359, a novel small-molecule LIFR inhibitor, against Type II ECa. The analysis of tumor databases has uncovered a correlation between diminished survival rates and increased expression of leukemia inhibitory factor (LIF), suggesting a potential connection between altered LIF expression and unfavorable overall survival in Type II ECa. The results obtained from cell viability and colony formation assays demonstrated a significant decrease in the growth of Type II ECa LIFR knockdown cells in comparison to vector control cells. Furthermore, in both primary and established Type II ECa cells, pharmacological inhibition of the LIF/LIFR axis with EC359 markedly decreased cell viability, long-term cell survival, and invasion, and promoted apoptosis. Additionally, EC359 treatment reduced the activation of pathways driven by LIF/LIFR, such as AKT, mTOR, and STAT3. Tumor progression was markedly inhibited by EC359 treatment in two different patient-derived xenograft models in vivo and patient-derived organoids ex vivo. Collectively, these results suggest LIFR inhibitor EC359 as a possible new small-molecule therapeutics for the management of Type II ECa.

Continuous ambulatory peritoneal dialysis peritonitis: Microbiology and outcomes.

Context: Continuous ambulatory peritoneal dialysis (CAPD) is now a preferred mode of the treatment in patients with end-stage renal disease, but peritonitis remains to be a shortcoming of CAPD. High-culture negativity, emerging drug resistance and peritoneal dialysis (PD)-related morbidity and mortality have been a challenge to tackle. Aims: The present study was taken up to compare the the various culture methods and to identify the spectrum of organisms causing CAPD peritonitis and their outcome. Settings and Design: A prospective, observational, cross-sectional study was conducted at a tertiary care teaching hospital in Hyderabad over a period of 1 year. Subjects and Methods: Dialysate fluid from 100 episodes of clinically suspected peritonitis in 75 patients was processed by conventional centrifuging, water lysis, direct inoculation and addition of centrifuged pellet into brain-heart infusion broth and by automated blood culture system. Identification and antibiotic susceptibility of organisms was done, and the outcome of PD-related peritonitis was analysed. Statistical Analysis Used: The categorical data and continuous data were analysed using the Chi-square test and Student's t-test, respectively. P < 0.05 was considered statistically significant. Results: Of the 100 PD fluids, 87 were culture positive. Automated blood culture systems detected 87 episodes, whereas conventional centrifuge method detected only 53 episodes (P = 0.00001). Peritonitis due to Gram-negative organisms (62.3%) was higher than that of Gram-positive peritonitis (31.1%) and fungi (6.4%). Nineteen per cent episodes were constituted by relapse (9), refractory (4), recurrent (4) and repeat (2) peritonitis. Outcomes were analysed as recovery (77%), catheter removal (15%) and death (2.6%). Conclusions: Direct inoculation of peritoneal fluid into automated blood culture bottles increases the positivity rate and also aids in the early detection of CAPD peritonitis, helping reduce morbidity and mortality of PD patients.

Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers.

BACKGROUND: CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) are approved for the treatment of ER+ advanced breast cancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. We previously reported a novel therapeutic agent, ERX-11, that binds to the estrogen receptor (ER) and modulates ER-coregulator interactions. Here, we tested if the combination of ERX-11 with agents approved for ER+ BCa would be more potent. METHODS: We tested the effect of combination therapy using BCa cell line models, including those that have acquired resistance to tamoxifen, letrozole, or CDK4/6 inhibitors or have been engineered to express mutant forms of the ER. In vitro activity was tested using Cell Titer-Glo, MTT, and apoptosis assays. Mechanistic studies were conducted using western blot, reporter gene assays, RT-qPCR, and mass spectrometry approaches. Xenograft, patient-derived explants (PDEs), and xenograft-derived explants (XDE) were used for preclinical evaluation and toxicity. RESULTS: ERX-11 inhibited the proliferation of therapy-resistant BCa cells in a dose-dependent manner, including ribociclib resistance. The combination of ERX-11 and CDK4/6 inhibitor was synergistic in decreasing the proliferation of both endocrine therapy-sensitive and endocrine therapy-resistant BCa cells, in vitro, in xenograft models in vivo, xenograft-derived explants ex vivo, and in primary patient-derived explants ex vivo. Importantly, the combination caused xenograft tumor regression in vivo. Unbiased global mass spectrometry studies demonstrated profound decreases in proliferation markers with combination therapy and indicated global proteomic changes in E2F1, ER, and ER coregulators. Mechanistically, the combination of ERX-11 and CDK4/6 inhibitor decreased the interaction between ER and its coregulators, as evidenced by immunoprecipitation followed by mass spectrometry studies. Biochemical studies confirmed that the combination therapy significantly altered the expression of proteins involved in E2F1 and ER signaling, and this is primarily driven by a transcriptional shift, as noted in gene expression studies. CONCLUSIONS: Our results suggest that ERX-11 inhibited the proliferation of BCa cells resistant to both endocrine therapy and CDK4/6 inhibitors in a dose-dependent manner and that the combination of ERX-11 with a CDK4/6 inhibitor may represent a viable therapeutic approach.

Recent Advances in Copper Intercalators as Anticancer Agents.

Copper is a part of various enzymes and helps them to function properly. It can be effectively used to produce promising anticancer drugs and presently, many studies are being pursued worldwide on the development of copper-based complexes as potential anticancer drugs. Herein, we briefly discuss the importance of reactive oxygen species in biological applications and copper(II) complexes as anticancer drugs. The anti-angiogenic properties of mono-nuclear copper(II) complexes have been demonstrated by in vivo chick embryo angiogenesis analysis. The plausible mechanism behind anticancer activity of these complexes is by the formation of excessive intracellular Reactive Oxygen Species (ROS). ROS is a composite term used for oxygen derivative non-radicals and free radicals of highly reactive components, that enhances the killing response of immune cells to microbial invasion. Previous reports have shown that ROS plays an important role as a messenger in cell cycling and normal cell signal transduction. Graphical Abstract The generation of singlet oxygen and healing the tumor cells with singlet oxygen in presence of UV-light.

Growth of children with food allergies in Singapore

BACKGROUND: Although it is known that children with food allergies are at risk of impaired growth, this has not been well studied in South-East Asia. OBJECTIVE: The aim of this cross-sectional study is to survey the growth of children with food allergies in Singapore and the factors impacting it. METHODS: Anthropometric data, demographic data, type of food allergy, foods eliminated, and atopic comorbidities were recorded. Malnutrition was defined using World Health Organization standards (≤-2 z-score for weight-for-height [WH], weight-for-age [WA], and height-for-age [HA]).

Cashew nut allergy in Singaporean children

BACKGROUND: There has been an increasing trend of nut allergies in Singapore. OBJECTIVE: The aim of this study was to review the clinical characteristics of children with cashew nut allergy. METHODS: A retrospective analysis was conducted in a tertiary paediatric referral centre in Singapore from 2008 to 2015. A total of 99 subjects with positive specific IgE (≥0.35 IU/L) to cashew nut were identified. Clinical features including demographics, clinical reaction to cashew nut, associations with other nuts and test specific measurements were recorded. RESULTS: The results showed that cutaneous symptoms (71.2%) were the most common allergic manifestations. Anaphylaxis occurred in 3.8% of children. In addition, all cashew nut allergic subjects were cross-reactive (either sensitized or allergic) to pistachio. Cross-reactivity rate with peanuts was 53.8%. There was a strong prevalence of atopy among cashew nut allergic subjects. CONCLUSION: In conclusion, cashew nut allergy is a significant tree nut allergy in Singapore.

Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers.

The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.

Correlation Between Molecular Modelling and Spectroscopic Techniques in Investigation With DNA Binding Interaction of Ruthenium(II) Complexes.

The DNA binding studies of rutheniumu(II) polypyridyl complexes {[Ru(phen)2Mipc]2+, [Ru(bpy)2Mipc]2+, [Ru(dmb)2Mipc]2+, [Ru(phen)2BrIPC]2+, [Ru(bpy)2BrIPC]2+, [Ru(dmb)2BrIPC]2+, [Ru(phen)2PIP-Cl]2+, [Ru(bpy)2PIP-Cl]2+, [Ru(dmb)2PIP-Cl]2+, [Ru(phen)2IPPBA]2+, [Ru(bpy)2IPPBA]2+, [Ru(dmb)2IPPBA]2+} with DNA investigated by electronic absorption titration, emission and molecular modelling studies to identify the binding interactions. All these complexes are showing good binding constant values ~104 to 105. The intercalative ligands makes the binding of the ruthenium(II) complex with DNA as intercalation mode. The ancillary ligands 1,10-phenanthroline (phen), 4,4'-Dimethyl-2,2'-dipyridyl (dmb) and 2,2'-dipyridine (bpy) having been discovered found to be involved in bond formation with the phosphate backbone of nucleotide base pairs in ruthenium(II) complex-DNA docked complex. The molecular docking results are good agreement with experimental results. The molecular modelling technic should help to extend knowledge about the nature (or) mode of binding of these ruthenium(II) complexes with (calf thymus) CT-DNA.

Selective Estrogen Receptor ß Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma.

Glioblastomas (GBM), deadly brain tumors, have greater incidence in males than females. Epidemiological evidence supports a tumor suppressive role of estrogen; however, estrogen as a potential therapy for GBM is limited due to safety concerns. Since GBM express ERß, a second receptor for estrogen, targeting ERß with a selective agonist may be a potential novel GBM therapy. In the present study, we examined the therapeutic effect of the selective synthetic ERß agonist LY500307 using in vitro and in vivo GBM models. Treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes in vitro. ERß agonists promoted apoptosis of GBM cells, and mechanistic studies using RNA sequencing revealed that LY500307 modulated several pathways related to apoptosis, cell cycle, and DNA damage response. Further, LY500307 sensitized GBM cells to several FDA-approved chemotherapeutic drugs including cisplatin, lomustine and temozolomide. LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of GBM tumors in an orthotopic model and improved the overall survival of tumor-bearing mice in the GL26 syngeneic glioma model. Our results demonstrate that LY500307 has potential as a therapeutic agent for GBM.

A stepwise approach in the management of chronic spontaneous urticaria in children

BACKGROUND: There is limited literature in the management of chronic urticaria in children. Treatment algorithms are generally extrapolated from adult studies. OBJECTIVE: Utility of a weight and age-based algorithm for antihistamines in management of chronic spontaneous urticaria (CSU) in childhood. To document associated factors that predict for step of control of CSU and time taken to attain control of symptoms in children. METHODS: A workgroup comprising of allergists, nurses, and pharmacists convened to develop a stepwise treatment algorithm in management of children with CSU. Sequential patients presenting to the paediatric allergy service with CSU were included in this observational, prospective study. RESULTS: Ninety-eight patients were recruited from September 2012 to September 2013. Majority were male, Chinese with median age 4 years 7 months. A third of patients with CSU had a family history of acute urticaria. Ten point two percent had previously resolved CSU, 25.5% had associated angioedema, and 53.1% had a history of atopy. A total of 96.9% of patients achieved control of symptoms, of which 91.8% achieved control with cetirizine. Fifty percent of all the patients were controlled on step 2 or higher. Forty-seven point eight percent of those on step 2 or higher were between 2 to 6 years of age compared to 32.6% and 19.6% who were 6 years and older and lesser than 2 years of age respectively. Eighty percent of those with previously resolved CSU required an increase to step 2 and above to achieve chronic urticaria control. CONCLUSION: We propose a weight- and age-based titration algorithm for different antihistamines for CSU in children using a stepwise approach to achieve control. This algorithm may improve the management and safety profile for paediatric CSU patients and allow for review in a more systematic manner for physicians dealing with CSU in children.

Tolerance to etoricoxib in children with nonsteroidal anti-inflammatory drug hypersensitivity

BACKGROUND: Cyclooxygenase-2 (COX-2) inhibitors have been found to be safe alternatives in adults with cross-intolerant hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). However they are usually not prescribed in children and there is little information about their tolerance in the pediatric age group. OBJECTIVE: This study aims to evaluate the tolerance to etoricoxib in children with hypersensitivity to multiple antipyretics. METHODS: A retrospective case series of children diagnosed with hypersensitivity reactions to NSAIDs and/or paracetamol who underwent a drug provocation test (DPT) with etoricoxib. Information on atopy, family history of allergic diseases, and medication usage was collected. Outcomes of the DPTs and tolerance to etoricoxib were also evaluated. RESULTS: A total of 24 children, mean age 13.5 years, had a diagnosis of cross-intolerant hypersensitivity to NSAIDs and/or paracetamol. All except one patient successfully tolerated an oral challenge with etoricoxib. Of those who passed the DPT, the majority continued to use etoricoxib with no problems. It was found to be moderately effective in reducing fever and pain. CONCLUSION: Etoricoxib can be used as a safe alternative in older children with hypersensitivity to multiple antipyretics.

Oxidative stress in non-obese women with polycystic ovarian syndrome.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of the most common endocrine diseases of women. Oxidative stress is an important component of the cardio-metabolic risk seen in these women. Oxidative stress has been reported in obese PCOS women. This study is taken up to study oxidative stress in non-obese PCOS women. MATERIALS AND METHODS: Twenty five non-obese women with PCOS attending the Endocrinology outpatient Department of Sri Venkateswara Institute of Medical Sciences, Tirupati, India along with 25 healthy BMI matched controls were included in the study. The changes in the lipid peroxidation products (MDA), and total anti oxidant capacity (FRAP) as an index of anti oxidant status along with fasting glucose, insulin and uric acid levels were measured in both groups. Insulin resistance was evaluated by using homeostasis model assessment for insulin resistance [HOMA-IR)= [FPG (mg/dl) × insulin (mIU/L)]/ 405] in both groups. RESULTS: Serum MDA and uric acid levels were increased in the study group compared with controls and FRAP levels were decreased in the study group compared to controls though statistically insignificant. CONCLUSION: Oxidative stress is also present in non-obese women with PCOS. Oxidative stress further increases the CVD risk in these women.Correcting oxidative stress with antioxidants along with monitoring the antioxidant status using a simple assay like FRAP could have a beneficial effect on oxidative stress induced insulin resistance and hyperandrogenism seen in these women.

Inhibition of mTOR signaling reduces PELP1-mediated tumor growth and therapy resistance.

Proline, Glutamic acid-, and Leucine-rich Protein 1 (PELP1) is a proto-oncogene that modulates estrogen receptor (ER) signaling. PELP1 expression is upregulated in breast cancer, contributes to therapy resistance, and is a prognostic marker of poor survival. In a subset of breast tumors, PELP1 is predominantly localized in the cytoplasm and PELP1 participates in extranuclear signaling by facilitating ER interactions with Src and phosphoinositide 3-kinase (PI3K). However, the mechanism by which PELP1 extranuclear actions contributes to cancer progression and therapy resistance remains unclear. In this study, we discovered that PELP1 cross-talked with the serine/threonine protein kinase mTOR and modulated mTOR signaling. PELP1 knockdown significantly reduced the activation of mTOR downstream signaling components. Conversely, PELP1 overexpression excessively activated mTOR signaling components. We detected the presence of the mTOR signaling complex proteins in PELP1 immunoprecipitates. mTOR-targeting drugs (rapamycin and AZD8055) significantly reduced proliferation of PELP1-overexpressed breast cancer cells in both in vitro and in vivo xenograft tumor models. MCF7 cells that uniquely retain PELP1 in the cytoplasm showed resistance to hormonal therapy and mTOR inhibitors sensitized PELP1cyto cells to hormonal therapy in xenograft assays. Notably, immunohistochemical studies using xenograft tumors derived from PELP1 overexpression model cells showed increased mTOR signaling and inhibition of mTOR rendered PELP1-driven tumors to be highly sensitive to therapeutic inhibition. Collectively, our data identified the PELP1-mTOR axis as a novel component of PELP1 oncogenic functions and suggest that mTOR inhibitor(s) will be effective chemotherapeutic agents for downregulating PELP1 oncogenic functions.

Gum pigmentation: an unusual adverse effect of sublingual immunotherapy

Sublingual immunotherapy has gained acceptance amongst the paediatric community as it is very well tolerated and is safe. The adverse effects of this therapy is minimal consisting mainly of local side effects within the oral cavity such as itching of the mouth, swelling of the lips and less frequently abdominal pain, wheezing and urticaria has been described. This report is to highlight another local side effect of sublingual immunotherapy which has been observed in 3 of our patients. This is pigmentation of the gums which can occur anytime during the course of the immunotherapy. It resolves on stopping the immunotherapy and is likely due to a local inflammatory process occurring in the gums of these children. There is no associated pain or itching with the pigmentation. It can persist as long as the child is on the immunotherapy.

Branched chain amino acid profile in early chronic kidney disease.

The nutritional status in chronic kidney disease (CKD) patients is a predictor of prognosis during the first period of dialysis. Serum albumin is the most commonly used nutritional marker. Another index is plasma amino acid profile. Of these, the plasma levels of branched chain amino acids (BCAA), especially valine and leucine, correlate well with nutritional status. Plasma BCAAs were evaluated along with albumin and C-reactive protein in 15 patients of early stages of CKD and 15 age- and sex-matched healthy controls. A significant decrease in plasma valine, leucine and albumin levels was observed in CKD patients when compared with the controls (P <0.05). No significant difference in C-reactive protein (CRP) levels was observed between the two groups. Malnutrition seen in our CKD patients in the form of hypoalbuminemia and decreased concentrations of BCAA points to the need to evaluate the nutritional status in the early stages itself. Simple measures in the form of amino acid supplementation should be instituted early to decrease the morbidity and mortality before start of dialysis in these patients.

Therapeutic significance of estrogen receptor ß agonists in gliomas.

Gliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two estrogen receptor (ER) subtypes: ERα, which functions as tumor promoter, and ERß, which functions as tumor suppressor. We examined the potential use of ERß agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ERß with little or no ERα. Treatment of glioma cells with ERß agonists resulted in significant decrease in proliferation. Immunohistochemical analysis of tumor tissues revealed that ERß expression is downregulated in high-grade gliomas. We found that ERß agonists promote both expression and tumor-suppressive functions of ERß in glioma cells. Liquiritigenin, a plant-derived ERß agonist significantly reduced in vivo tumor growth in a xenograft model. Compared with control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. Immunohistochemical analysis of tumors revealed a significant increase in the nuclear ERß expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ERß signaling has a tumor-suppressive function in gliomas. Because ERß agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERß agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients.

Increased expression of macrophage colony-stimulating factor and its receptor in patients with endometriosis.

OBJECTIVE: To investigate the expression and regulation of colony-stimulating factor 1 (CSF-1) and its receptor, C-FMS, in endometriosis. DESIGN: In vivo and vitro study. SETTING: University-based academic medical center. PATIENT(S): Reproductive-age women undergoing surgery for benign conditions. INTERVENTION(S): Peritoneal and endometrial tissue samples were obtained. MAIN OUTCOME MEASURE(S): CSF-1 and C-FMS expression. RESULT(S): Significantly higher CSF-1 levels were found in peritoneal fluid of patients with endometriosis compared with control subjects. Ectopic endometriotic tissue had 3.5-fold and 1.7-fold increases in CSF-1 and C-FMS expression, respectively, compared with eutopic tissue. Coculture of endometrial cells from either established cell lines or patient samples with peritoneal mesothelial cells (PMCs) led to increased expression of CSF-1 and C-FMS. A higher but nonsignificant increase in levels of C-FMS and CSF-1 was found in cocultures of endometrial epithelial cells from patients with endometriosis compared with those without endometriosis. CONCLUSION(S): Increased CSF-1 levels may contribute to endometriosis lesion formation and progression. Elevation in CSF-1 after coculture of endometrial cells with PMCs suggests that endometrial tissue may be a source of peritoneal CSF-1. Increased C-FMS expression in endometrial cells from women with endometriosis cocultured with PMCs suggests that endometrial tissue involved in lesion formation is highly responsive to CSF-1 signaling.

Estrogen receptor-beta mediates the protective effects of aromatase induction in the MMTV-Her-2/neu x aromatase double transgenic mice.

Breast cancers amplified for the tyrosine kinase receptor Her-2/neu constitute ~30% of advanced breast cancer cases, and are characterized by hormone independence and aggressive growth, implicating this pathway in breast oncogenesis. The induction of Her-2/neu leads to tumor development in 60% of transgenic mice. We have previously examined the effects of estrogen in the MMTV-Her-2/neu background by generating the MMTV-Her-2/neu x aromatase double transgenic mouse strain. MMTV-Her-2/neu x aromatase mice developed fewer mammary tumors than the Her-2/neu parental strain. Our present data show the induction of several estrogen-related genes, including the tumor suppressors BRCA1 and p53, and a decrease in several angiogenic factors. The phosphorylated forms of MAPK p42/44 and AKT were lower in the MMTV-Her-2/neu x aromatase double transgenic mice compared to the MMTV-Her-2/neu parental strain; conversely, phospho-p38 levels were higher in the double transgenic strain. The ERß-selective antagonist THC reversed these changes. The regulation of these factors by ERß was confirmed in clones of MCF7 breast cancer cells overexpressing Her-2/neu in combination with ERß, suggesting that ERß may play a direct role in regulating MAPK and AKT pathways. In summary, the data suggest that ERß may play a major role in decreasing tumorigenesis and that it may affect breast cancer cell proliferation and survival by altering MAPK and AKT activation as well as modulation of tumor suppressor and angiogenesis factors. Treatment with selective ERß agonist may provide therapeutic advantages for the treatment and prevention of breast cancer.

Colony-stimulating factor-1 exerts direct effects on the proliferation and invasiveness of endometrial epithelial cells.

Although macrophage colony-stimulating factor (CSF-1) has been suggested to play a role in maintaining the chronic inflammatory response in endometriosis, our data suggest that CSF-1 may also play a role in early endometriosis lesion formation. We have shown that CSF-1, in an autocrine fashion, has a direct effect on endometrial epithelial cell proliferation and attachment to peritoneal mesothelial cells, early steps in endometriosis lesion formation on the peritoneum.

Estrogen receptor-ß activation in combination with letrozole blocks the growth of breast cancer tumors resistant to letrozole therapy.

Treatment with anti-estrogens or aromatase inhibitors (AI) is the main therapeutic strategy used against estrogen receptor ERα-positive breast cancer. Resistance to these therapies presents a major challenge in the management of breast cancer. Little is known about ERß in breast carcinogenesis. Our aim in this study is to examine potential novel strategies utilizing ERß activity to overcome AI resistance. We provide evidence that ERß agonist can reduce the growth of AI-resistant breast cancer cells. Our data further confirm that therapeutic activation of ERß by DPN, an ERß agonist, blocks letrozole-resistant tumor growth in a xenograft model. Interestingly, DPN exerted tumor growth inhibition only in the presence of the AI letrozole, suggesting that combination therapy including ERß activators and AI may be used in the clinical setting treating AI resistant breast cancer. An increase in ERß levels, with diminished ERα/ERß ratio, was observed in the tumors from mice treated with DPN/letrozole combination compared to single agents and control. Decreased Cyclin D1 and increased CyclinD1/CDK inhibitors p21 and p27 levels in DPN/letrozole treated tumors were observed, suggesting that the combination treatment may inhibit tumor growth by blocking G1/S phase cell cycle progression. Our data show a decrease in MAPK phosphorylation levels without affecting total levels. In addition to providing evidence suggesting the potential use of ERß agonists in combination with letrozole in treating AI resistant breast cancer and prolonging sensitivity to AI, we also provide mechanistic evidence supporting the role of ERß in altering the expression profile associated with resistance.