Aryl hydrocarbon receptor knockout accelerates PanIN formation and fibro-inflammation in a mutant -driven pancreatic cancer model.

Objectives: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the pathogenesis of several cancers, and can be targeted for therapeutic effect. However, its involvement in PDAC remains unclear.

Sox9 in mouse urogenital sinus epithelium mediates elongation of prostatic buds and expression of genes involved in epithelial cell migration.

Previous studies identified Sox9 as a critical mediator of prostate development but the precise stage when Sox9 acts had not been determined. A genetic approach was used to delete Sox9 from mouse urogenital sinus epithelium (UGE) prior to prostate specification. All prostatic bud types (anterior, dorsolateral and ventral) were stunted in Sox9 conditional knockouts (cKOs) even though the number of prostatic buds did not differ from that of controls.

Common basis for orofacial clefting and cortical interneuronopathy.

Orofacial clefts (OFCs) of the lip and/or palate are among the most common human birth defects. Current treatment strategies focus on functional and cosmetic repair but even when this care is available, individuals born with OFCs are at high risk for persistent neurobehavioral problems. In addition to learning disabilities and reduced academic achievement, recent evidence associates OFCs with elevated risk for a constellation of psychiatric outcomes including anxiety disorders, autism spectrum disorder, and schizophrenia.

Gene-environment interactions in cortical interneuron development and dysfunction: A review of preclinical studies.

Cortical interneurons (cINs) are a diverse group of locally projecting neurons essential to the organization and regulation of neural networks. Though they comprise only ∼20% of neurons in the neocortex, their dynamic modulation of cortical activity is requisite for normal cognition and underlies multiple aspects of learning and memory. While displaying significant morphological, molecular, and electrophysiological variability, cINs collectively function to maintain the excitatory-inhibitory balance in the cortex by dampening hyperexcitability and synchronizing activity of projection neurons, primarily through use of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

Regulation of the latent-lytic switch in Epstein-Barr virus.

Epstein-Barr virus (EBV) infection contributes to the development of several different types of human malignancy, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. As a herpesvirus, EBV can establish latent or lytic infection in cells. EBV-positive tumors are composed almost exclusively of cells with latent EBV infection.

Association of cellular and molecular responses in the rat mammary gland to 17β-estradiol with susceptibility to mammary cancer.

Background: We are using ACI and BN rats, which differ markedly in their susceptibility to 17β-estradiol (E2)-induced mammary cancer, to identify genetic variants and environmental factors that determine mammary cancer susceptibility. The objective of this study was to characterize the cellular and molecular responses to E2 in the mammary glands of ACI and BN rats to identify qualitative and quantitative phenotypes that associate with and/or may confer differences in susceptibility to mammary cancer.

Methods: Female ACI and BN rats were treated with E2 for 1, 3 or 12 weeks.

Research resource: global identification of estrogen receptor β target genes in triple negative breast cancer cells.

Breast cancers that are negative for estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 are known as triple-negative breast cancers (TNBC). TNBCs are associated with an overall poor prognosis because they lack expression of therapeutic targets like ERα and are biologically more aggressive. A second estrogen receptor, ERβ, has been found to be expressed in 50% to 90% of ERα-negative breast cancers, and ERβ expression in TNBCs has been shown to correlate with improved disease-free survival and good prognosis.

CARM1 automethylation is controlled at the level of alternative splicing.

Co-activator-associated arginine methyltransferase 1 (CARM1) is subjected to multiple post-translational modifications. Our previous finding that automethylation of CARM1 is essential for regulation of transcription and pre-mRNA splicing prompted us to investigate how automethylation is regulated. Here, we report that automethylation is regulated by alternative splicing of CARM1 mRNA to remove exon 15, containing the automethylation site.

Differential action of monohydroxylated polycyclic aromatic hydrocarbons with estrogen receptors α and β.

Polycyclic aromatic hydrocarbons (PAHs) are a diverse group of widespread environmental pollutants, some of which have been found to be estrogenic or antiestrogenic. Recent data have shown that hydroxylated PAH metabolites may be responsible for the estrogenic effects of some PAHs. The purpose of this study was to investigate the effects of several PAHs, as well as their monohydroxylated metabolites, on estrogen receptors (ERs), ERα and ERβ.

Roles of the envelope proteins in the amplification of covalently closed circular DNA and completion of synthesis of the plus-strand DNA in hepatitis B virus.

Covalently closed circular DNA (cccDNA), the nuclear form of hepatitis B virus (HBV), is synthesized by repair of the relaxed circular (RC) DNA genome. Initially, cccDNA is derived from RC DNA from the infecting virion, but additional copies of cccDNA are derived from newly synthesized RC DNA molecules in a process termed intracellular amplification. It has been shown that the large viral envelope protein limits the intracellular amplification of cccDNA for duck hepatitis B virus.

The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions.

Introduction: Mechanisms underlying low-penetrance, common, non-protein coding variants in breast cancer risk loci are largely undefined. We showed previously that the non-protein coding mammary carcinoma susceptibility locus Mcs5a/MCS5A modulates breast cancer risk in rats and women. The Mcs5a allele from the Wistar-Kyoto (WKy) rat strain consists of two genetically interacting elements that have to be present on the same chromosome to confer mammary carcinoma resistance.

Endocrine disrupting chemicals targeting estrogen receptor signaling: identification and mechanisms of action.

Many endocrine disrupting chemicals (EDCs) adversely impact estrogen signaling by interacting with two estrogen receptors (ERs): ERα and ERβ. Though the receptors have similar ligand binding and DNA binding domains, ERα and ERβ have some unique properties in terms of ligand selectivity and target gene regulation. EDCs that target ER signaling can modify genomic and nongenomic ER activity through direct interactions with ERs, indirectly through transcription factors such as the aryl hydrocarbon receptor (AhR), or through modulation of metabolic enzymes that are critical for normal estrogen synthesis and metabolism.

Human papillomavirus type 16 E6 and E7 oncoproteins act synergistically to cause head and neck cancer in mice.

High-risk human papillomaviruses (HPVs) contribute to cervical and other anogenital cancers, and they are also linked etiologically to a subset of head and neck squamous cell carcinomas (HNSCC). We previously established a model for HPV-associated HNSCC in which we treated transgenic mice expressing the papillomaviral oncoproteins with the chemical carcinogen 4-nitroquinoline-1-oxide (4-NQO). We found that the HPV-16 E7 oncoprotein was highly potent in causing HNSCC, and its dominance masked any potential oncogenic contribution of E6, a second papillomaviral oncoprotein commonly expressed in human cancers.

Selectively targeting estrogen receptors for cancer treatment.

Estrogens regulate growth and development through the action of two distinct estrogen receptors (ERs), ERα and ERβ, which mediate proliferation and differentiation of cells. For decades, ERα mediated estrogen signaling has been therapeutically targeted to treat breast cancer, most notably with the selective estrogen receptor modulator (SERM) tamoxifen. Selectively targeting ERs occurs at two levels: tissue selectivity and receptor subtype selectivity.

Longitudinal assessment of colonic tumor fate in mice by computed tomography and optical colonoscopy.

Rationale And Objectives: The purpose of this study was to evaluate the relative merits of micro-computed tomograph colonography (mCTC) and optical colonoscopy (OC) for longitudinal studies of colonic tumors in mice.

Materials And Methods: Colonic tumors in mice carrying the Min allele of Apc were followed over several weeks using mCTC and OC. A total of 146 colonic tumors were monitored: 62 in 32 untreated Min mice, 53 in 43 Min mice treated with 5-fluorouracil (5-FU), and 31 in 17 Min mice treated with piroxicam.

Wnt signaling can substitute for estrogen to induce division of ERalpha-positive cells in a mouse mammary tumor model.

The interaction of estrogen with the estrogen receptor (ER, principally ERalpha) induces growth of human breast tumor cells. In contrast, ERalpha-positive cells have been described as non-dividing cells in normal breast (though estrogen stimulation of ERalpha cells directs the division of neighboring cells). However, there is a small sub-population of cells in normal mammary tissue that are ERalpha-positive, that can divide, and therefore share this property with human breast tumor cells.

Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17.

Sex hormones influence the susceptibility of inbred mice to liver cancer. C57BR/cdJ (BR) females are extremely susceptible to spontaneous and chemically induced liver tumors, in part due to a lack of protection against hepatocarcinogenesis normally offered by ovarian hormones. BR males are also moderately susceptible, and the susceptibility of both sexes of BR mice to liver tumors induced with N,N-diethylnitrosamine relative to the resistant C57BL/6J (B6) strain is caused by two loci designated Hcf1 and Hcf2 (hepatocarcinogenesis in females) located on chromosomes 17 and 1, respectively.

The microRNAs of Epstein-Barr Virus are expressed at dramatically differing levels among cell lines.

Epstein-Barr Virus (EBV) encodes multiple microRNAs (miRNAs) from two primary transcripts, BHRF1 and the BARTs. The expression of BHRF1 miRNAs is dependent on the type of viral latency, whereas the BART miRNAs are expressed in cells during all forms of latency. It is not known how these miRNAs are otherwise regulated, though.

Intermolecular interactions identify ligand-selective activity of estrogen receptor alpha/beta dimers.

Estrogen receptor (ER) dimerization is prerequisite for its activation of target gene transcription. Because the two forms of ER, ERalpha and ERbeta, exhibit opposing functions in cell proliferation, the ability of ligands to induce ERalpha/beta heterodimers vs. their respective homodimers is expected to have profound impacts on transcriptional outcomes and cellular growth.

Large-scale Epstein-Barr virus EBNA1 protein purification.

The protein-DNA and protein-protein interactions of Epstein-Barr virus nuclear antigen 1 (EBNA1) are known to play an important role in the many functions of this viral protein. Large quantities of pure EBNA1 protein would be useful in biochemical assays to elucidate such interactions. In particular, the crystal structure of the full-length protein would be important to show possible regions of interaction and/or post-translational modification.

Base behavior behind budding breasts: integrins and mammary stem cell activity.

In a recent Nature Cell Biology paper, Taddei et al. (2008) reveal that deletion of beta1 integrin from K5-expressing mammary epithelial basal cells specifically attenuates ductal stem cell activity, without dramatically altering the basal cell layer, or morphogenesis overall.

Intestinal adenomagenesis involves core molecular signatures of the epithelial-mesenchymal transition.

The epithelial-mesenchymal transition (EMT) occurs commonly during carcinoma invasion and metastasis, but not during early tumorigenesis. Microarray data demonstrated elevation of vimentin, a mesenchymal marker, in intestinal adenomas from Apc Min/+ (Min) mice. We have tested the involvement of EMT in early tumorigenesis in mammalian intestines by following EMT-associated markers.

Reproducibility of tumor volume measurement at microCT colonography in living mice.

Rationale And Objectives: We sought to demonstrate the viability of microcomputed tomographic colonography (muCTC) as a tool for monitoring tumorigenesis in mouse models of human colorectal cancer during prospective longitudinal studies. The precision and accuracy of volumetric measurements were determined to assess whether changes in tumor volume over time were readily detectable.

Materials And Methods: All animal studies were conducted under the guidelines set forth by the Institutional Animal Care and Use Committee of the American Association for Assessment and Accreditation of Laboratory Animal Care.