Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer.

Background: The human epidermal growth factor receptor (HER) family of transmembrane tyrosine kinases is overexpressed and correlates with poor prognosis and decreased survival in many cancers. The receptor family has been therapeutically targeted, yet tyrosine kinase inhibitors (TKIs) do not inhibit kinase-independent functions and antibody-based targeting does not affect internalized receptors. We have previously demonstrated that a peptide mimicking the internal juxtamembrane domain of HER1 (EGFR; EJ1) promotes the formation of non-functional HER dimers that inhibit kinase-dependent and kinase-independent functions of HER1 (ERBB1/EGFR), HER2 (ERBB2) and HER3 (ERBB3).

Intravesicular epidermal growth factor receptor subject to retrograde trafficking drives epidermal growth factor-dependent migration.

The Epidermal Growth Factor Receptor (EGFR) is frequently mutated and overexpressed in metastatic cancer. Although EGFR is a transmembrane tyrosine kinase localized to the basolateral membrane in normal epithelium, it is frequently found intracellularly localized in transformed cells. We have previously demonstrated the epithelial adaptor protein mucin 1 (MUC1) alters trafficking of EGFR, inhibiting its degradation and promoting its translocation to the nucleus, where it can directly modulate gene transcription.

Methylation of inorganic arsenic by murine fetal tissue explants.

Although it is generally believed that the developing fetus is principally exposed to inorganic arsenic and the methylated metabolites from the maternal metabolism of arsenic, little is known about whether the developing embryo can autonomously metabolize arsenic. This study investigates inorganic arsenic methylation by murine embryonic organ cultures of the heart, lung, and liver. mRNA for AS3mt, the gene responsible for methylation of arsenic, was detected in all embryonic tissue types studied.

Arsenite Disrupts Zinc-Dependent TGFβ2-SMAD Activity During Murine Cardiac Progenitor Cell Differentiation.

TGFβ2 (transforming growth factor-β2) is a key growth factor regulating epithelial to mesenchymal transition (EMT). TGFβ2 triggers cardiac progenitor cells to differentiate into mesenchymal cells and give rise to the cellular components of coronary vessels as well as cells of aortic and pulmonary valves. TGFβ signaling is dependent on a dynamic on and off switch in Smad activity.

Inactive ERBB receptors cooperate with reactive oxygen species to suppress cancer progression.

The ERBB receptors are a family of heterodimerization partners capable of driving transformation and metastasis. While the therapeutic targeting of single receptors has proven efficacious, optimal targeting of this receptor family should target all oncogenic members simultaneously. The juxtamembrane domains of ERBB1, ERBB2, and ERBB3 are highly conserved and control various aspects of ERBB-dependent biology.

Disruption of canonical TGFβ-signaling in murine coronary progenitor cells by low level arsenic.

Exposure to arsenic results in several types of cancers as well as heart disease. A major contributor to ischemic heart pathologies is coronary artery disease, however the influences by environmental arsenic in this disease process are not known. Similarly, the impact of toxicants on blood vessel formation and function during development has not been studied.

MUC1 drives c-Met-dependent migration and scattering.

The transmembrane mucin MUC1 is overexpressed in most ductal carcinomas, and its overexpression is frequently associated with metastatic progression. MUC1 can drive tumor initiation and progression via interactions with many oncogenic partners, including β-catenin, the EGF receptor (EGFR) and Src. The decoy peptide protein transduction domain MUC1 inhibitory peptide (PMIP) has been shown to inhibit the tumor promoting activities of MUC1 in breast and lung cancer, including cell growth and invasion, and its usage suppresses metastatic progression in mouse models of breast cancer.

Chronic low-level arsenite exposure through drinking water increases blood pressure and promotes concentric left ventricular hypertrophy in female mice.

Cardiovascular disease is the leading cause of death in the United States and worldwide. High incidence of cardiovascular diseases has been linked to populations with elevated arsenic content in their drinking water. Although this correlation has been established in many epidemiological studies, a lack of experimental models to study mechanisms of arsenic-related cardiovascular pathogenesis has limited our understanding of how arsenic exposure predisposes for development of hypertension and increased cardiovascular mortality.

Arsenic exposure perturbs epithelial-mesenchymal cell transition and gene expression in a collagen gel assay.

Arsenic is a naturally occurring metalloid and environmental contaminant. Arsenic exposure in drinking water is reported to cause cancer of the liver, kidneys, lung, bladder, and skin as well as birth defects, including neural tube, facial, and vasculogenic defects. The early embryonic period most sensitive to arsenic includes a variety of cellular processes.

An improved protocol for the isolation and cultivation of embryonic mouse myocytes.

In vitro cultures of cardiomyocytes have proven to be a useful tool for toxicological, pharmacological, and developmental studies, as well as for the study of the cellular and molecular mechanisms responsible for proper myocyte function. One deficient area of research is that of myocyte proliferation. Cardiomyocyte proliferation dramatically diminishes soon after birth and has a very limited occurrence within the adult heart, thus limiting the use of adult cells for proliferation studies.

MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis.

Congenital heart defects occur at a rate of 5% and are the most prevalent birth defects. A better understanding of the complex signaling networks regulating heart development is necessary to improve repair strategies for congenital heart defects. The mitogen-activated protein 3 kinase (MEKK3) is important to early embryogenesis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully examined.

Depolymerized hyaluronan induces vascular endothelial growth factor, a negative regulator of developmental epithelial-to-mesenchymal transformation.

Cardiac malformations constitute the most common birth defects, of which heart septal and valve defects are the most frequent forms diagnosed in infancy. These cardiac structures arise from the endocardial cushions through dynamic interactions between cells and the extracellular matrix (cardiac jelly). Targeted deletion of the hyaluronan synthase-2 (Has2) gene in mice results in an absence of hyaluronan (HA), cardiac jelly, and endocardial cushions, a loss of vascular integrity, and death at embryonic day 9.