EGF AND TGF-ALPHA MODULATE STRUCTURAL AND FUNCTIONAL-DIFFERENTIATION OF THE MAMMARY-GLAND FROM PREGNANT MICE IN-VITRO - POSSIBLE ROLE OF THE ARACHIDONIC-ACID PATHWAY

Epidermal growth factor (EGF) has been suggested to be involved in mam mary gland development by mitogenic stimulation of the ductal and alve olar epithelium in virgin mice. The present studies demonstrate that a lso in late-pregnant mice EGF leads to proliferation of the ductal, du ctular, and alveolar epithelium. The mitogenic effect is associated wi th structural and functional dedifferentiation of alveolar cells as re vealed by analysis of morphology, expression of cytosolic and secretor y proteins, and fatty acid synthesis. Using a combination of metabolic inhibitors, the dedifferentiating effect of EGF could be blocked whil e the mitogenic action was not influenced. This finding demonstrates t hat the signal transduction pathway leading to dedifferentiation and m itosis can be separated, and that the dedifferentiating effect of EGF is independent of its mitogenic properties, but is probably mediated b y activation of the arachidonic acid-dependent pathways (cyclo- and li poxygenase pathways). Release of arachidonic acid from the endogenous phospholipid pool was found to be an early response of the explants to EGF. Accordingly, arachidonic acid itself proved to be capable of ind ucing epithelial dedifferentiation but failed to stimulate proliferati on. TGF alpha showed qualitatively similar effects as EGF but was gene rally a stronger agonist. It is suggested that EGF and TGF alpha also play a role in mammary gland physiology during pregnancy by final deve loping and maintanance of the lobulo-alveolar structure in the mammary gland and prevention of premature onset of lactation, and that this i s mediated through the PLA(2)-arachidonic acid signalling cascade. (C) 1995 Wiley-Liss, Inc.