Lrig1 is an estrogen-regulated growth suppressor and correlates with longer relapse-free survival in ERα-positive breast cancer.

Lrig1 is the founding member of the Lrig family and has been implicated in the negative regulation of several oncogenic receptor tyrosine kinases including ErbB2. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some prostate and colorectal tumors. Given this heterogeneity, whether Lrig1 functions to suppress or promote tumor growth remains a critical question.

Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression.

The aryl hydrocarbon receptor (AhR) has been best known for its role in mediating the toxicity of dioxin. Here we show that AhR overexpression is found among estrogen receptor (ER)α-negative human breast tumors and that its overexpression is positively correlated to that of the NF-κB subunit RelB and Interleukin (IL)-8. Increased DNA binding activity of the AhR and RelB is coupled to IL-8 overexpression in primary breast cancer tissue, which was also supported by in situ hybridization.

Post-transcriptional mechanisms contribute to the suppression of the ErbB3 negative regulator protein Nrdp1 in mammary tumors.

The ErbB2 and ErbB3 receptor tyrosine kinases act synergistically to promote cellular properties associated with tumor development. Previous studies indicate that endogenous ErbB3 protein is markedly elevated in mouse mammary tumors induced by transgenic ErbB2 overexpression. However, this occurs in the absence of elevated ErbB3 transcript, indicating that post-transcriptional regulatory mechanisms play crucial roles in suppressing ErbB3 protein in normal tissue.

The membrane mucin MUC4 is elevated in breast tumor lymph node metastases relative to matched primary tumors and confers aggressive properties to breast cancer cells.

Introduction: Previous studies indicate that overexpression of the membrane-associated mucin MUC4 is potently anti-adhesive to cultured tumor cells, and suppresses cellular apoptotic response to a variety of insults. Such observations raise the possibility that MUC4 expression could contribute to tumor progression or metastasis, but the potential involvement of MUC4 in breast cancer has not been rigorously assessed. The present study aimed to investigate the expression of the membrane mucin MUC4 in normal breast tissue, primary breast tumors and lymph node metastases, and to evaluate the role of MUC4 in promoting the malignant properties of breast tumor cells.

Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer.

The ErbB2 receptor tyrosine kinase is overexpressed in approximately 25% of breast tumors and contributes to poor patient prognosis and therapeutic resistance. Here, we examine the role of the recently discovered ErbB negative regulator LRIG1 in ErbB2(+) breast cancer. We observe that LRIG1 protein levels are significantly suppressed in ErbB2-induced mammary tumors in transgenic mice as well as in the majority of ErbB2(+) human breast tumors.

Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells.

Her2 is overexpressed in 20% to 30% of breast tumors and correlates with reduced disease-free and overall patient survival. Trastuzumab, a humanized monoclonal antibody directed against Her2, represents the first Her2-targeted therapy, which decreases the risk of relapse and prolongs patient survival. Resistance to trastuzumab, both inherent and treatment-acquired, represents a significant barrier to the effective treatment of Her2 (+) breast cancer.

LRIG1 is a novel negative regulator of the Met receptor and opposes Met and Her2 synergy.

The Met receptor tyrosine kinase regulates a complex array of cellular behaviors collectively known as "invasive growth." While essential for normal development and wound repair, this program is frequently co-opted by tumors to promote their own growth, motility, and invasion. Met is overexpressed in a variety of human tumors, and this aberrant expression correlates with poor patient prognosis.

ErbB receptor negative regulatory mechanisms: implications in cancer.

Activation of ErbB receptor tyrosine kinases (RTKs) must be precisely regulated to ensure the fidelity of developmental and homeostatic processes mediated by growth factors. Insufficient receptor stimulation will lead to defects in tissue development, while excessive stimulation can lead to hyperplastic events associated with cancer and other diseases. A coordinated balance of the intensity and timing of receptor signaling, achieved through both receptor activation and negative regulatory mechanisms, is required for signaling fidelity.

The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3.

Mucins provide a protective barrier for epithelial surfaces, and their overexpression in tumors has been implicated in malignancy. We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1beta (NRG1beta) growth factor. In the present study we demonstrate that Muc4 expression in A375 human melanoma cells, as well as MCF7 and T47D human breast cancer cells, enhances NRG1beta signaling through the phosphatidylinositol 3-kinase pathway.

Structure of the nucleotide complex of PyrR, the pyr attenuation protein from Bacillus caldolyticus, suggests dual regulation by pyrimidine and purine nucleotides.

PyrR is a protein that regulates the expression of genes and operons of pyrimidine nucleotide biosynthesis (pyr genes) in many bacteria. PyrR acts by binding to specific sequences on pyr mRNA and causing transcriptional attenuation when intracellular levels of uridine nucleotides are elevated. PyrR from Bacillus subtilis has been purified and extensively studied.

Functional oligomeric state of avian sarcoma virus integrase.

Retroviral integrase, one of only three enzymes encoded by the virus, catalyzes the essential step of inserting a DNA copy of the viral genome into the host during infection. Using the avian sarcoma virus integrase, we demonstrate that the enzyme functions as a tetramer. In presteady-state active site titrations, four integrase protomers were required for a single catalytic turnover.

A dimeric mechanism for contextual target recognition by MutY glycosylase.

MutY, an adenine glycosylase, initiates the critical repair of an adenine:8-oxo-guanine base pair in DNA arising from polymerase error at the oxidatively damaged guanine. Here we demonstrate for the first time, using presteady-state active site titrations, that MutY assembles into a dimer upon binding substrate DNA and that the dimer is the functionally active form of the enzyme. Additionally, we observed allosteric inhibition of glycosylase activity in the dimer by the concurrent binding of two lesion mispairs.

Flipping duplex DNA inside out: a double base-flipping reaction mechanism by Escherichia coli MutY adenine glycosylase.

The Escherichia coli MutY adenine glycosylase plays a critical role in repairing mismatches in DNA between adenine and the oxidatively damaged guanine base 8-oxoguanine. Crystallographic studies of the catalytic core domain of MutY show that the scissile adenine is extruded from the DNA helix to be bound in the active site of the enzyme (Guan, Y., Manuel, R.