Copper secretion from human breast epithelial cells is mediated by ATP7B and lactational hormones

Abstract

Mammary epithelial cells that produce milk are unique in containing both of the Cu pumps, ATP7A and B, central to mammalian copper homeostasis but otherwise found individually. We have begun studies to clarify their roles in this gland using confocal microscopy. ATP7B was expressed in the luminal epithelial cells of human breast tissue, with a perinuclear location that shifted to a diffuse location with lactation. In the human mammary epithelial cell culture model (PMC42), ATP7B was also in the perinuclear region and redistributed to endosomes adjacent to, but not coincident with, the apical plasma membrane after treatment of the cultures with a lactational hormone regimen (3 days estrogen and progesterone then 3 days insulin, dexamethasone, prolactin). ATP7B was in a different subset of vesicles from those containing milk proteins and did not overlap with endosomes containing ATP7A. A physiological concentration of extracellular Cu was required for the redistribution effect, suggesting it was caused indirectly by increased intracellular Cu concentrations. Overexpression of ATP7B in the PMC42 cultures, grown as polarized monolayers, resulted in an enhanced efflux of Cu from the apical cell surface (determined with 64Cu). Our findings are consistent with the concept that ATP7B is important for the secretion of copper from the mammary gland into the milk. Supported by PHS Grant No. RO1 HD 46949.