The growth of solid tumors is characterized by insufficient delivery of oxygen and nutrients. This creates a cytotoxic tumor microenvironment that affects intracellular energy and redox homeostasis interfering with the proper folding of transmembrane and secretory proteins within the endoplasmic reticulum (ER). Accumulation of misfolded proteins in the ER triggers activation of the unfolded protein response (UPR) signal transduction pathway. The PKR-like ER kinase (PERK) is an ER resident serine/threonine kinase that mediates pro-survival signaling during UPR. UPR signaling mechanisms facilie maintenance of the normal physiology of secretory tissues. Studies in knockout mice revealed that PERK is necessary for survival of secretory cells of the pancreas. In the mammary gland, another secretory tissue, ER protein load is increased significantly during pregnancy and lactation. We hypothesize that PERK-mediated pro-survival signaling is critical during these postnatal stages of mammary gland development. We will develop a mammary gland-specific PERK knockout employing the MMTV-Cre/LoxP PERK system and utilize this mouse model to investigate the role of PERK in mammary gland development. We further propose that PERK facilitates breast cancer cell survival such that PERK inactivation compromises breast tumor growth and progression. We will establish a mammary gland-specific PERK knockout/Neu transgenic mouse strain. This model will allow us to address the role of PERK in breast tumorigenesis. ? ? ? ?
