ROLE OF PKC IN CELL TURNOVER IN THE MAMMARY GLAND

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Mammary gland development and involution are complex processes which are regulated in part through dynamic changes in cell proliferation and apoptosis. In the mammary gland apoptosis contributes to ductal development and is essential for the clearance of mammary epithelial cells during post-lactational involution. Protein kinase Cdelta (PKCdelta) is a ubiquitously expressed isoform of the PKC family of serine/threonine kinases, and analysis of the mouse knock-out of PKCdelta suggests that this isoform regulates both cell proliferation and apoptosis. Our studies indicate that PKCdelta functions early in the apoptotic pathway and we have recently identified Signal Transducer and Activator of Transcription 1 (STAT1) as a downstream target of PKCdelta in apoptotic cells. PKCdelta is also essential for STAT3 activation in cells treated with cytokines and interferon. In the mammary gland, STATS is required for mammary gland development during pregnancy, while STATS orchestrates mammary gland involution. The central role PKCdelta plays in epithelial cell apoptosis, together with the link between PKC5 and STAT activation, suggests that PKCdelta may be critical for mammary gland homeostasis. In this proposal we will explore the role of PKCdelta in mammary gland development and involution using mice in which the PKCdelta gene has been disrupted (deltaKO mice) and primary mammary epithelial cells derived from wild type and deltaKO mice. In Aim 1 we will test the hypothesis that loss of PKCdelta in vivo result in suppression or delay of involution and may result in abnormal mammary gland development. We will determine if mammary gland development and/or involution are altered in PKCdelta knock-out (deltaKO) mice, if the mammary gland phenotype in the deltaKO mice is tissue autonomous, and if reconstitution of PKCdelta can reverse the phenotype. In Aim 2 we will explore the molecular mechanisms by which PKCdelta regulates mammary epithelial cell apoptosis, and we will test the hypothesis that PKCdelta is required for signal transduction downstream of prolactin and the IL6 family cytokines. We will explore PKCdelta activation in response to apoptotic stimuli relevant to involution and determine the functional domains of PKCdelta that are required for apoptosis in MECs. We will determine if MECs from deltaKO mice are resistant to apoptosis induced by these stimuli and explore the molecular mechanism which underlies this resistance. The proposed studies will enhance our understanding of the signal transduction pathways which regulate mammary gland development and involution.