cIAP2 Is an Independent Signaling and Survival Factor during Mammary Lactational Involution and Tumorigenesis

AbstractCellular inhibitor of apoptosis proteins-1 and -2 (cIAP1/2) are integral to regulation of apoptosis and signaling by the tumor necrosis factor (TNF) and related family of receptors. The expression of cIAP2 in tissues is typically low and considered functionally redundant with cIAP1, however cIAP2 can be activated by a variety of cellular stresses. Members of the TNFR family and their ligands have essential roles in mammary gland biology. We have found thatcIAP2−/− virgin mammary glands have reduced ductal branching and delayed lobuloalveogenesis in early pregnancy. Post-lactational involution involves two phases where the first phase is reversible and is mediated, in part, by TNFR family ligands. IncIAP2 −/− mice mammary glands appeared engorged at mid-lactation accompanied by enhanced autophagic flux and decreased cIAP1 protein expression. Severely stretched myoepithelium was associated with BIM-EL expression and other indicators of anoikis. Within 24  h after forced or natural weaning,cIAP2−/− glands had nearly completed involution. The TNF-related weak inducer of apoptosis (Tweak) which results in degradation of cIAP1 through its receptor, Fn14, began to increase in late lactation and was significantly increased incIAP2−/− relative to WT mice by 12  h post weaning accompanied by decreased cIAP1 protein expression. Carcinogen/progesterone-induced mammary tumorigenesis was significantly delayed incIAP2−/− mice and tumors contained high numbers o...
Source: Journal of Mammary Gland Biology and Neoplasia - Category: Cancer & Oncology Source Type: research