Role of polyunsaturated fatty acids as signal transducers: Amplification of signals from growth factor receptors by fatty acids in mammary epithelial cells

The growth, morphogenesis and differentiation of milk producing epithelial tissues in the developing mammary glands require interaction with extracellular matrices and stimulation by hormones, growth factors and essential fatty acids. In primary culture, the proliferation of mammary epithelial cells (MEC), induced by epidermal growth factor (EGF), is enhanced and sustained by linoleate and its eicosanoid metabolites. Since a combination of linoleic acid (18:2ω6) and prostaglandin E 2 or cAMP has synergistic effect on EGF-stimulated growth, it is suggested that additional cAMP-dependent protein kinase A (PK-A) independent pathways may also contribute to the linoleate effect on EGF action. Possible involvement of Ca2+phospholipid-dependent protein kinase C (PK-C) is explored. Both linoleate and arachidonate can activate Type-II and Type-III protein kinase-C in MEC and a PK-C inhibitor can block growth stimulation by EGF and fatty acids. Like 12-O-Tetradecanoly phorbol-13-acetate (TPA), a PK-C activator which also enhances EGF-stimulated growth of MEC, linoleate can phosphorylate a 40–42 KD protein. EGF itself can stimulate transient phosphorylation of the same protein in MEC cultures but when supplemented with linoleate, which does not influence the ligand binding affinity of EGF-receptors, the transient phosphorylation signal in 40–42 KD protein is sustained. Based on our results and other published reports, it is proposed that although both EGF and essential fatty acid (EFA) evoke multiple pathways in cells, serine/threonine kinase activity of PK-C and PK-A and tyrosine kinase activity of EGF-receptors may converge in the phosphorylation of 40–42 KD type of protein which could be a downstream messenger of EGF and EFA action.