Consideration of GREB1 as a potential therapeutic target for hormone-responsive or endocrine-resistant cancers.

Introduction: Steroid hormones increase the incidence and promote the progression of many types of cancer. Exogenous estrogens increase the risk of developing breast, ovarian and endometrial cancer and many breast cancers initially respond to estrogen deprivation. Although steroid hormone signaling has been extensively studied, the mechanisms of hormone-stimulated cancer growth have not yet been fully elucidated, limiting opportunities for novel approaches to therapeutic intervention.

Loss of UCHL1 promotes age-related degenerative changes in the enteric nervous system.

UCHL1 (ubiquitin carboxyterminal hydrolase 1) is a deubiquitinating enzyme that is particularly abundant in neurons. From studies of a spontaneous mutation arising in a mouse line it is clear that loss of function of UCHL1 generates profound degenerative changes in the central nervous system, and it is likely that a proteolytic deficit contributes to the pathology. Here these effects were found to be recapitulated in mice in which the Uchl1 gene had been inactivated by homologous recombination.

Differential effects of glyoxalase 1 overexpression on diabetic atherosclerosis and renal dysfunction in streptozotocin-treated, apolipoprotein E-deficient mice.

The reactive dicarbonyls, glyoxal and methylglyoxal (MG), increase in diabetes and may participate in the development of diabetic complications. Glyoxal and MG are detoxified by the sequential activities of glyoxalase 1 (GLO1) and glyoxalase 2. To determine the contribution of these dicarbonyls to the etiology of complications, we have genetically manipulated GLO1 levels in apolipoprotein E-null (Apoe(-/-)) mice.

Hypothesis: a role for EBV-induced molecular mimicry in Parkinson's disease.

Current concepts regarding the pathogenesis of Parkinson's disease support a model whereby environmental factors conspire with a permissive genetic background to initiate the disease. The identity of the responsible environmental trigger has remained elusive. There is incontrovertible evidence that aggregation of the neuronal protein alpha-synuclein is central to disease pathogenesis.

Protection against murine osteoarthritis by inhibition of the 26S proteasome and lysine-48 linked ubiquitination.

Objectives: To determine whether the process of ubiquitination and/or activity of the 26S proteasome are involved in the induction of osteoarthritis (OA).

Methods: Bovine cartilage resorption assays, chondrocyte cell-line SW1353 and primary human articular chondrocytes were used with the general proteasome inhibitor MG132 or vehicle to identify a role of the ubiquitin-proteasome system (UPS) in cartilage destruction and matrix metalloproteinase-13 (MMP13) expression. In vivo, MG132 or vehicle, were delivered subcutaneously to mice following destabilisation of the medial meniscus (DMM)-induced OA.

A new spontaneously transformed syngeneic model of high-grade serous ovarian cancer with a tumor-initiating cell population.

Improving screening and treatment options for patients with epithelial ovarian cancer has been a major challenge in cancer research. Development of novel diagnostic and therapeutic approaches, particularly for the most common subtype, high-grade serous ovarian cancer (HGSC), has been hampered by controversies over the origin of the disease and a lack of spontaneous HGSC models to resolve this controversy. Over long-term culture in our laboratory, an ovarian surface epithelial (OSE) cell line spontaneously transformed OSE (STOSE).

Targeting TBP-Associated Factors in Ovarian Cancer.

As ovarian tumors progress, they undergo a process of dedifferentiation, allowing adaptive changes in growth and morphology that promote metastasis and chemoresistance. Herein, we outline a hypothesis that TATA-box binding protein associated factors (TAFs), which compose the RNA Polymerase II initiation factor, TFIID, contribute to regulation of dedifferentiation states in ovarian cancer. Numerous studies demonstrate that TAFs regulate differentiation and proliferation states; their expression is typically high in pluripotent cells and reduced upon differentiation.

17β-estradiol upregulates GREB1 and accelerates ovarian tumor progression in vivo.

Exogenous 17β-estradiol (E2) accelerates the progression of ovarian cancer in the transgenic tgCAG-LS-TAg mouse model of the disease. We hypothesized that E2 has direct effects on ovarian cancer cells and this study was designed to determine the molecular mechanisms by which E2 accelerates ovarian tumor progression. Mouse ovarian cancer ascites (MAS) cell lines were derived from tgCAG-LS-TAg mice.

Alpha-synuclein in the appendiceal mucosa of neurologically intact subjects.

Parkinson's disease is characterized by the pathological aggregation of Alpha-synuclein. The dual-hit hypothesis proposed by Braak implicates the enteric nervous system as an initial site of α-synuclein aggregation with subsequent spread to the central nervous system. Regional variations in the spatial pattern or levels of α-synuclein along the enteric nervous system could have implications for identifying sites of onset of this pathogenic cascade.

SIRT1 catalytic activity has little effect on tumor formation and metastases in a mouse model of breast cancer.

The protein deacetylase SIRT1 has been implicated in the regulation of a large number of cellular processes that are thought to be required for cancer initiation and progression. There are conflicting data that make it unclear whether Sirt1 functions as an oncogene or tumor suppressor. To assess the effect of SIRT1 on the emergence and progression of mammary tumors, we crossed mice that harbor a point mutation that abolishes SIRT1 catalytic activity with mice carrying the polyoma middle T transgene driven by the murine mammary tumor virus promoter (MMTV-PyMT).

Structural disorder and the loss of RNA homeostasis in aging and neurodegenerative disease.

Whereas many cases of neurodegenerative disease feature the abnormal accumulation of protein, an abundance of recent literature highlights loss of RNA homeostasis as a ubiquitous and central feature of pathological states. In some diseases expanded repeats have been identified in non-coding regions of disease-associated transcripts, calling into question the relevance of protein in the disease mechanism. We review the literature in support of a hypothesis that intrinsically disordered proteins (proteins that lack a stable three dimensional conformation) are particularly sensitive to an age-related decline in maintenance of protein homeostasis.

PTEN loss represses glioblastoma tumor initiating cell differentiation via inactivation of Lgl1.

Glioblastoma multiforme is an aggressive and incurable type of brain tumor. A subset of undifferentiated glioblastoma cells, known as glioblastoma tumor initiating cells (GTICs), has an essential role in the malignancy of this disease and also appears to mediate resistance to radiation therapy and chemotherapy. GTICs retain the ability to differentiate into cells with reduced malignant potential, but the signaling pathways controlling differentiation are not fully understood at this time.

Lovastatin-induced apoptosis is mediated by activating transcription factor 3 and enhanced in combination with salubrinal.

We have previously demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to induce tumor-specific apoptosis. The apoptotic effects of lovastatin were regulated in part by the integrated stress response (ISR) that regulates cellular responses to a wide variety of stress inducers. A key regulator of the ISR apoptotic response is activating transcription factor 3 (ATF3) and its target gene CHOP/GADD153.

Novel variant of neuronal intranuclear rodlet immunoreactive for 40 kDa huntingtin associated protein and ubiquitin in the mouse brain.

Intranuclear rodlets (INRs), also known as rodlets of Roncoroni, are poorly understood intranuclear bodies originally identified within neuronal nuclei on the basis of their unique morphology. The mechanisms of their formation, their biochemical composition and their physiological significance remain unknown. Using double immunofluorescence staining of mouse brain sections, we identified a novel variant of INR that is immunoreactive for the 40 kDa huntingtin associated protein (Hap40) and ubiquitin, and provide evidence for the existence of additional INR subtypes sharing ubiquitin immunoreactivity as a common feature.

Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes.

Unlabelled: NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRAS(G12D)) in mouse melanocytes. When NRAS(G12D) was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi but did not induce cutaneous melanoma.

Bone-Targeted Agents for the Management of Breast Cancer Patients with Bone Metastases.

Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or treatment-related complications. Bone metastases predispose patients to reduced survival, pain, impaired quality of life and the development of skeletal-related events.

Technical challenges and limitations of current mouse models of ovarian cancer.

The development of genetically engineered models (GEM) of epithelial ovarian cancer (EOC) has been very successful, with well validated models representing high grade and low grade serous adenocarcinomas and endometrioid carcinoma (EC). Most of these models were developed using technologies intended to target the ovarian surface epithelium (OSE), the cell type long believed to be the origin of EOC. More recent evidence has highlighted what is likely a more prevalent role of the secretory cell of the fallopian tube in the ontogeny of EOC, however none of the GEM of EOC have demonstrated successful targeting of this important cell type.

Lovastatin induces multiple stress pathways including LKB1/AMPK activation that regulate its cytotoxic effects in squamous cell carcinoma cells.

Background: Cellular stress responses trigger signaling cascades that inhibit proliferation and protein translation to help alleviate the stress or if the stress cannot be overcome induce apoptosis. In recent studies, we demonstrated the ability of lovastatin, an inhibitor of mevalonate synthesis, to induce the Integrated Stress Response as well as inhibiting epidermal growth factor receptor (EGFR) activation.

Methodology/principal Findings: In this study, we evaluated the effects of lovastatin on the activity of the LKB1/AMPK pathway that is activated upon cellular energy shortage and can interact with the above pathways.

Detection of PIK3CA Mutations in Breast Cancer Bone Metastases.

Background. An important goal of personalized cancer therapy is to tailor specific therapies to the mutational profile of individual patients. However, whole genome sequencing studies have shown that the mutational profiles of cancers evolve over time and often differ between primary and metastatic sites.

Enhancement of cisplatin cytotoxicity by disulfiram involves activating transcription factor 3.

Background: Activating transcription factor 3 (ATF3), a stress-inducible gene, is a regulator of cisplatin-induced cytotoxicity, and enhancement of the ATF3 expression potentiates this cytotoxicity.

Materials And Methods: ATF3 expression and its binding to the transcription target CHOP were evaluated by western blot and chromatin immunoprecipitation (ChIP), respectively, in a panel of five cell lines (WI38, MCF7, PC3, A549). MTT assays were employed to assess the effects of many drugs, including disulfiram, on cell viability.

How to decide whether to offer and use "nonstandard" therapies in patients with advanced sarcomas and gastrointestinal stromal tumors: global variations in clinical practice, assessment, and access to therapies in diseases with limited incidence and data.

As cancer is more generally recognized as a collection of various rare diseases rather than a homogeneous illness, sarcomas have become a model for the manner in which data can and cannot be used to drive clinical decision making. In this article, we explore the limitations of data generated in rare diseases such as sarcomas to provide an evidence base for clinical practice. How should patients be treated if there is no "standard" that offers "proof" of clinical benefit? By asking this question, we also raise the issue of what constitutes "clinical benefit"-and how to measure that-for patients with sarcomas and other rare diseases.

Sensitivity of cervical carcinoma cells to vesicular stomatitis virus-induced oncolysis: potential role of human papilloma virus infection.

High-risk carcinogenic subtypes of human papilloma virus (HPV) are associated with the development of squamous cell carcinomas of the cervix (CC) and a subset of head and neck (HNSCC). Recurrent metastatic diseases of these sites display a dismal prognosis. Therefore, there is an urgent need to uncover innovative therapeutic strategies in this clinical setting.