Excess ATP7A reduces the copper content of the mammary gland in pregnancy and lactation but does not alter levels of plasma ceruloplasmin

Abstract

Two Cu pumps, ATP7A and B, are critical for Cu transport and homeostasis in mammalian metabolism. Mammary gland (MG) and placenta are somewhat unique in expressing both ATPases, and the question arises as to their separate functions. We hypothesized that in the lactating MG, ATP7B promotes entry of Cu into the milk, while ATP7A promotes efflux of excess Cu back into the blood. In lactating human breast we showed with confocal microscopy that ATP7A was localized in the basolateral membrane. It moved towards the basolateral membrane from the TGN in response to lactational hormones in the PMC42 cell breast model. In transgenic mice with human ATP7A expression 10–20 fold higher than endogenous mouse Atp7a, total Cu in the mammary gland, brain and kidney was reduced. Hepatic Cu and plasma ceruloplasmin were unchanged; however, plasma ferroxidase activity was significantly higher in the transgenic animals. In lactation and throughout gestation, MG had half as much Cu as the wild type, as did the milk. Uptake of 64Cu tracer by MG 1h after i.p. injection increased about 3‐fold from early to late gestation in the wild type but was significantly lower in the ATP7A overexpressing mice. These findings are consistent with the concept that ATP7A promotes “backflow” of Cu from mammary epithelial cells to the maternal blood, not just in lactation but also during gestational mammary gland development. Supported by USPHS Grant HD 46949.