Loss of protein kinase C delta alters mammary gland development and apoptosis

Abstract

As apoptotic pathways are commonly deregulated in breast cancer, exploring how mammary gland cell death is regulated is critical for understanding human disease. We show that primary mammary epithelial cells from protein kinase C delta (PKCδ) −/− mice have a suppressed response to apoptotic agents in vitro. In the mammary gland in vivo, apoptosis is critical for ductal morphogenesis during puberty and involution following lactation. We have explored mammary gland development in the PKCδ −/− mouse during these two critical windows. Branching morphogenesis was altered in 4- to 6-week-old PKCδ −/− mice as indicated by reduced ductal branching; however, apoptosis and proliferation in the terminal end buds was unaltered. Conversely, activation of caspase-3 during involution was delayed in PKCδ −/− mice, but involution proceeded normally. The thymus also undergoes apoptosis in response to physiological signals. A dramatic suppression of caspase-3 activation was observed in the thymus of PKCδ −/− mice treated with irradiation, but not mice treated with dexamethasone, suggesting that there are both target- and tissue-dependent differences in the execution of apoptotic pathways in vivo. These findings highlight a role for PKCδ in both apoptotic and nonapoptotic processes in the mammary gland and underscore the redundancy of apoptotic pathways in vivo.

Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-δ

“…We have previously shown that PKCδ−/− mice are resistant to IR-induced damage to the salivary gland and thymus and have a delay in mammary gland involution, a process driven by apoptosis (6,11). Our studies demonstrate that phosphorylation of PKCδ at Y64 and Y155 by c-Src and c-Abl, respectively, drives nuclear translocation, and is necessary and sufficient for the pro-apoptotic function of PKCδ (5,7,8).…”

“…PKCδ −/− mice are protected from IR-induced damage to the salivary gland and thymus, and have a delay in mammary gland involution, a process driven by apoptosis (6,11). Likewise, salivary epithelial cells from PKCδ−/− mice are resistant to multiple apoptotic stimuli including IR (6,12).…”

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

“…While loss of PKCδ has been reported to reduce fertility, post-natal development of PKCδ−/− mice appears to be normal (Ma, Baumann, & Viveiros, 2015), although subtle developmental phenotypes have been reported. For instance, we show a transient delay in mammary gland development in PKCδ−/− mice, including reduced ductal branching (Allen-Petersen et al, 2010). Stress and disease related phenotypes have also been reported.…”

“…In vitro, salivary epithelial and smooth muscle cells isolated from PKCδ−/− mice are resistant to apoptotic stimuli (Leitges et al, 2001; Humphries et al, 2006). In vivo, PKCδ−/− mice are protected from irradiation-induced damage to the salivary gland and thymus and have a delay in mammary gland involution, a process driven by apoptosis (Humphries et al, 2006; Allen-Petersen et al, 2010). PKCδ can also contribute to apoptosis induced by death receptors including TRAIL and TNFα (Khwaja & Tatton, 1999; Gonzalez-Guerrico & Kazanietz, 2005; Yin, Sethi, & Reddy, 2010; Gordon, Anantharam, Kanthasamy, & Kanthasamy, 2012; Xu, Su, & Liu, 2012).…”

Protein kinase Cδ is required for ErbB2-driven mammary gland tumorigenesis and negatively correlates with prognosis in human breast cancer

“…PKCδ is an important regulator of epithelial cell apoptosis, which has led to the speculation that it may play a role in tumorigenesis (8–13). Increased expression of PKCδ has been shown in colon, pancreatic, and high-grade breast tumors (14–16).…”