Identification of New Mono/Dihydroxynaphthoquinone as Lead Agents That Inhibit the Growth of Refractive and Triple-Negative Breast Cancer Cell Lines.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in nearly 20-30% of breast cancers and is associated with metastasis resulting in poor patient survival and high recurrence. The dual EGFR/HER2 kinase inhibitor lapatinib has shown promising clinical results, but its limitations have also led to the resistance and activation of tumor survival pathways. Following our previous investigation of quinones as HER2 kinase inhibitors, we synthesized several naphthoquinone derivatives that significantly inhibited breast tumor cells expressing HER2 and trastuzumab-resistant HER2 oncogenic isoform, HER2Δ16.

Ablating ErbB4 in PV neurons attenuates synaptic and cognitive deficits in an animal model of Alzheimer's disease.

Accumulation of amyloid β (Aβ) induces neuronal, synaptic, and cognitive deficits in patients and animal models of Alzheimer's disease (AD). The underlying mechanisms, however, remain to be fully elucidated. In the present study, we found that Aβ interacted with ErbB4, a member of the receptor tyrosine kinase family and mainly expressed in GABAergic interneurons.

Trastuzumab stimulation of ribosomal protein S6 kinase 1 (S6K1) predicts de novo trastuzumab resistance.

Breast cancer is a complex disease with at least five different molecular subtypes identified. The breast tumor molecular subtypes guide stratification of patients for specific targeted therapy regimens and each subtype is associated with significantly different patient outcomes. For example, patients with the HER2 positive molecular subtype benefit from the HER2 targeted therapy trastuzumab.

Intrinsic HER4/4ICD transcriptional activation domains are required for STAT5A activated gene expression.

The epidermal growth factor receptor family member HER4 undergoes proteolytic processing at the cell surface to release the HER4 intracellular domain (4ICD) nuclear protein. Interestingly, 4ICD directly interacts with STAT5 and functions as an obligate STAT5 nuclear chaperone. Once in the nucleus 4ICD binds with STAT5 at STAT5 target genes, dramatically potentiating STAT5 transcriptional activation.

The transcription factor NeuroD2 coordinates synaptic innervation and cell intrinsic properties to control excitability of cortical pyramidal neurons.

Key Points: Synaptic excitation and inhibition must be properly balanced in individual neurons and neuronal networks to allow proper brain function. Disrupting this balance may lead to autism spectral disorders and epilepsy. We show the basic helix-loop-helix transcription factor NeuroD2 promotes inhibitory synaptic drive but also decreases cell-intrinsic neuronal excitability of cortical pyramidal neurons both in vitro and in vivo.

MicroRNA-7 inhibits multiple oncogenic pathways to suppress HER2Δ16 mediated breast tumorigenesis and reverse trastuzumab resistance.

The oncogenic isoform of HER2, HER2Δ16, is expressed with HER2 in nearly 50% of HER2 positive breast tumors where HER2Δ16 drives metastasis and resistance to multiple therapeutic interventions including tamoxifen and trastuzumab. In recent years microRNAs have been shown to influence multiple aspects of tumorigenesis and tumor cell response to therapy. Accordingly, the HER2Δ16 oncogene alters microRNA expression to promote endocrine resistance.

A class of genes in the HER2 regulon that is poised for transcription in breast cancer cell lines and expressed in human breast tumors.

HER2-positive breast cancer accounts for 25% of all cases and has a poor prognosis. Although progress has been made in understanding signal transduction, little is known of how HER2 achieves gene regulation. We performed whole genome expression analysis on a HER2⁺ and HER2⁻ breast cancer cell lines and compared these results to expression in 812 primary tumors stratified by their HER2 expression level.

Hypoxia-inducible factor-1α induces ErbB4 signaling in the differentiating mammary gland.

Conditional knock-out of Hif1a in the mouse mammary gland impairs lobuloalveolar differentiation during lactation. Here, we demonstrate that expression of ErbB4 was reduced in the lobulalveoli of mice with mammary gland-specific deletion of Hif1a. Erbb4 was not, however, a direct target gene for transcriptional regulation by HIF-1α in vitro.

Basal cell signaling by p63 controls luminal progenitor function and lactation via NRG1.

The mammary epithelium is organized as a bilayer of luminal and basal/myoepithelial cells. During pregnancy, the luminal compartment expands for milk production, while basal cells are thought to provide structural and contractile support. Here, we reveal a pregnancy-specific role of basal epithelia as a central coordinator of lactogenesis.

Identification of quinones as HER2 inhibitors for the treatment of trastuzumab resistant breast cancer.

HER2 overexpression is associated with aggressive breast cancer with high recurrence rate and poor patient prognosis. Treatment of HER2 overexpressing patients with the HER2 targeting therapy trastuzumab results in acquired resistance within a year. The HER2/EGFR dual kinase inhibitor lapatinib was shown to inhibit some trastuzumab resistant breast cancer cell lines and is currently in clinical trials.

HER4 selectively coregulates estrogen stimulated genes associated with breast tumor cell proliferation.

The EGFR-family member HER4 undergoes regulated intramembrane proteolysis (RIP) to generate an intracellular domain (4ICD) that functions as a transcriptional coactivator. Accordingly, 4ICD coactivates the estrogen receptor (ER) and associates with ER at target gene promoters in breast tumor cells. However, the extent of 4ICD coactivation of ER and the functional significance of the 4ICD/ER transcriptional complex is unclear.

Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling.

The receptor-tyrosine kinase ErbB4 was identified as a direct regulator of hypoxia-inducible factor-1α (HIF-1α) signaling. Cleaved intracellular domain of ErbB4 directly interacted with HIF-1α in the nucleus, and stabilized HIF-1α protein in both normoxic and hypoxic conditions by blocking its proteasomal degradation. The mechanism of HIF stabilization was independent of VHL and proline hydroxylation but dependent on RACK1.

Jumonji/ARID1 B (JARID1B) protein promotes breast tumor cell cycle progression through epigenetic repression of microRNA let-7e.

MicroRNAs (miRs) function as tumor suppressors or oncogenes in multiple tumor types. Although miR expression is tightly regulated, the molecular basis of miR regulation is poorly understood. Here, we investigated the influence of the histone demethylase Jumonji/ARID1 B (JARID1B) on miR regulation in breast tumor cells.

The ERBB4 intracellular domain (4ICD) regulates NRG1-induced gene expression in hippocampal neurons.

The NRG1 growth factor and ERBB4 receptor have been identified as leading schizophrenia risk genes. Although NRG1 and ERBB4 have been shown to modulate neuronal functions involved in schizophrenia, including both GABAergic and glutamatergic synapses, the exact molecular mechanisms remain poorly understood. Here we investigated ERBB4 intracellular domain, 4ICD, transactivator function in rat hippocampal cultures by inhibiting γ-secretase mediated ERBB4 regulated intramembrane proteolysis (RIP).

Neuregulin receptor ErbB4 functions as a transcriptional cofactor for the expression of surfactant protein B in the fetal lung.

Sufficient pulmonary surfactant production is required for the fetal-neonatal transition, especially in preterm infants. Neuregulin (NRG) and its transmembrane receptor ErbB4 positively regulate the onset of fetal surfactant synthesis. Details of this signaling process remain to be elucidated.

Downregulation of miR-342 is associated with tamoxifen resistant breast tumors.

Background: Tumor resistance to the selective estrogen receptor modulator tamoxifen remains a serious clinical problem especially in patients with tumors that also overexpress HER2. We have recently demonstrated that the clinically important isoform of HER2, HERΔ16, promotes therapeutically refractory breast cancer including resistance to endocrine therapy. Likewise additional breast tumor cell models of tamoxifen resistance have been developed that do not involve HER2 overexpression.

Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of the p38 mitogen-activated protein kinase signaling pathway.

Introduction: The pineal gland hormone, melatonin, has been shown by numerous studies to inhibit the proliferation of estrogen receptor α (ERα)-positive breast cancer cell lines. Here, we investigated the role of melatonin in the regulation of breast cancer cell invasion.

Methods: Three invasive MCF-7 breast cancer cell clones - MCF-7/6, MCF-7/Her2.

Oncogenic HER2{Delta}16 suppresses miR-15a/16 and deregulates BCL-2 to promote endocrine resistance of breast tumors.

Tamoxifen is the most commonly prescribed therapy for patients with estrogen receptor (ER)α-positive breast tumors. Tumor resistance to tamoxifen remains a serious clinical problem especially in patients with tumors that also overexpress human epidermal growth factor receptor 2 (HER2). Current preclinical models of HER2 overexpression fail to recapitulate the clinical spectrum of endocrine resistance associated with HER2/ER-positive tumors.

The ERalpha coactivator, HER4/4ICD, regulates progesterone receptor expression in normal and malignant breast epithelium.

The HER4 intracellular domain (4ICD) is a potent estrogen receptor (ERalpha) coactivator with activities in breast cancer and the developing mammary gland that appear to overlap with progesterone receptor (PgR). In fact, 4ICD has recently emerged as an important regulator and predictor of tamoxifen response, a role previously thought to be fulfilled by PgR. Here we investigated the possibility that the 4ICD coactivator regulates PgR expression thereby providing a mechanistic explanation for their partially overlapping activities in breast cancer.

Subcellular localization of the HER4 intracellular domain, 4ICD, identifies distinct prognostic outcomes for breast cancer patients.

Conflicting reports of the prognostic value of HER4 in breast cancer may be explained by distinct activities of the HER4 intracellular domain, 4ICD. Here, immunohistochemical 4ICD staining of archival invasive breast cancers (n = 923) was scored separately for nuclear and cytosolic expression, and these data were tested for associations with clinicopathological markers, disease-free survival, and disease-specific survival. By univariate analysis, cytosolic 4ICD expression was independently associated with estrogen receptor and progesterone receptor expression and tumor cell apoptosis.

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance.

The HER2-targeted therapy trastuzumab is widely used for the treatment of patients with metastatic breast tumors overexpressing HER2. However, an objective response is observed in only 12% to 24% of patients treated with trastuzumab as a single agent and initial responders regress in <6 months (1-3). The reason for the clinical failure of trastuzumab in this setting remains unclear.

The HER4/4ICD estrogen receptor coactivator and BH3-only protein is an effector of tamoxifen-induced apoptosis.

Greater than 40% of breast cancer patients treated with tamoxifen exhibit de novo or acquired tumor resistance. Recent clinical evidence indicates that loss of expression of HER4 is an independent marker for tamoxifen resistance. In direct corroboration with clinical observations, suppression of HER4 expression in the tamoxifen-sensitive MCF-7 and T47D breast tumor cell lines resulted in resistance to tamoxifen-induced apoptosis.

HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer.

The HER4 receptor tyrosine kinase was the final member of the EGFR-family to be discovered. In contrast to the other three members of this receptor family which function primarily as mitogenic effectors in the breast, HER4 appears to have multiple divergent functions in the normal and malignant breast. Interestingly, the majority of HER4 activities in the breast including pregnancy induced differentiation and lactation initiation, transcriptional activation, tumor cell proliferation, growth suppression, and induction of apoptosis appear to be mediated by an independently signaling soluble HER4 intracellular domain (4ICD).