Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development

Seven classes of mitogen-activated protein kinase (MAPK) intracellular signalling cascades exist, four of which are implicated in breast disease and function in mammary epithelial cells. These are the extracellular regulated kinase (ERK)1/2 pathway, the ERK5 pathway, the p38 pathway and the c-Jun N-terminal kinase (JNK) pathway. In some forms of human breast cancer and in many experimental models of breast cancer progression, signalling through the ERK1/2 pathway, in particular, has been implicated as being important. We review the influence of ERK1/2 activity on the organised three-dimensional association of mammary epithelial cells, and in models of breast cancer cell invasion. We assess the importance of epidermal growth factor receptor family signalling through ERK1/2 in models of breast cancer progression and the influence of ERK1/2 on its substrate, the oestrogen receptor, in this context. In parallel, we consider the importance of these MAPK-centred signalling cascades during the cycle of mammary gland development. Although less extensively studied, we highlight the instances of signalling through the p38, JNK and ERK5 pathways involved in breast cancer progression and mammary gland development

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Opioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid μ receptors. A large number of biochemical and pharmacological studies and studies using genetically modified animals have provided convincing evidence regarding the existence of modulatory interactions between opioid μ and δ receptors. Several studies indicate that δ receptor agonists as well as δ receptor antagonists can provide beneficial modulation to the pharmacological effects of μ agonists. For example, δ agonists can enhance the analgesic potency and efficacy of μ agonists, and δ antagonists can prevent or diminish the development of tolerance and physical dependence by μ agonists. On the basis of these observations, the development of new opioid ligands possessing mixed μ agonist/δ agonist profile and mixed μ agonist/δ antagonist profile has emerged as a promising new approach to analgesic drug development. A brief overview of μ-δ interactions and recent developments in identification of ligands possessing mixed μ agonist/δ agonist and μ agonist/δ antagonist activities is provided in this report