Uncoupling of PI3K from ErbB3 impairs mammary gland development but does not impact on ErbB2-induced mammary tumorigenesis.

The formation of ErbB2/ErbB3 heterodimers plays a critical role in ErbB2-mediated signaling in both normal mammary development and mammary tumor progression. Through 7 phosphoinositide 3-kinase (PI3K) phosphotyrosine-binding sites, ErbB3 is able to recruit PI3K and initiate the PI3K/AKT signaling pathway. To directly explore the importance of the ErbB3/PI3K pathway in mammary development and tumorigenesis, we generated a mouse model that carries a mutant ErbB3 allele lacking the seven known PI3K-binding sites (ErbB3(Δ85)).

β1-integrins signaling and mammary tumor progression in transgenic mouse models: implications for human breast cancer.

Consistent with their essential role in cell adhesion to the extracellular matrix, integrins and their associated signaling pathways have been shown to be involved in cell proliferation, migration, invasion and survival, processes required in both tumorigenesis and metastasis. β1-integrins represent the predominantly expressed integrins in mammary epithelial cells and have been proven crucial for mammary gland development and differentiation. Here we provide an overview of the studies that have used transgenic mouse models of mammary tumorigenesis to establish β1-integrin as a critical mediator of breast cancer progression and thereby as a potential therapeutic target for the development of new anticancer strategies.

Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression.

Elevated expression and activation of the focal adhesion kinase (FAK) occurs in a large proportion of human breast cancers. Although several studies have implicated FAK as an important signaling molecule in cell culture systems, evidence supporting a role for FAK in mammary tumor progression is lacking. To directly assess the role of FAK in this process, we have used the Cre/loxP recombination system to disrupt FAK function in the mammary epithelium of a transgenic model of breast cancer.

Endocrine tumours of the gastrointestinal tract. Somatostatin receptors as tools for diagnosis and therapy: molecular aspects.

Somatostatin is a neuropeptide that acts as an endogenous inhibitor of various cellular functions including endocrine and exocrine secretions and the proliferation of normal and tumour cells. Its action is mediated by a family of G-protein-coupled receptors (sst1-sst5) that are widely distributed in normal and tumour cells. Gastroenteropancreatic endocrine tumours express multiple somatostatin receptors, sst2 being clearly predominant.

Restoration of functional gap junctions through internal ribosome entry site-dependent synthesis of endogenous connexins in density-inhibited cancer cells.

Gap junctions are composed of connexins and are critical for the maintenance of the differentiated state. Consistently, connexin expression is impaired in most cancer cells, and forced expression of connexins following cDNA transfection reverses the tumor phenotype. We have found that the restoration of density inhibition of human pancreatic cancer cells by the antiproliferative somatostatin receptor 2 (sst2) is due to overexpression of endogenous connexins Cx26 and Cx43 and consequent formation of functional gap junctions.

Molecular signaling of somatostatin receptors.

Somatostatin is a neuropeptide family that is produced by neuroendocrine, inflammatory, and immune cells in response to different stimuli. Somatostatin acts as an endogenous inhibitory regulator of various cellular functions including secretions, motility, and proliferation. Its action is mediated by a family of G-protein-coupled receptors (called sst1-sst5) that are widely distributed in the brain and periphery.

sst2 Somatostatin receptor inhibits cell proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2 activation.

The G protein-coupled sst2 somatostatin receptor is a critical negative regulator of cell proliferation. sstII prevents growth factor-induced cell proliferation through activation of the tyrosine phosphatase SHP-1 leading to induction of the cyclin-dependent kinase inhibitor p27Kip1. Here, we investigate the signaling molecules linking sst2 to p27Kip1.

Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein.

We report here that apelin (65-77) induces activation of extracellular-regulated kinases (ERKs) in Chinese hamster ovary (CHO) cells expressing the msr/apj receptor. This concentration-dependent activation was transient, peaking at 5 min. Pretreatment of CHO cells with pertussis toxin fully abrogated ERK phosphorylation, whereas overexpression of the beta-adrenergic receptor kinase-1 C-terminal fragment did not alter ERK activation.