Role and Regulation of TNF-Alpha in Normal Rat Mammary Gland During Development and in Breast Cancer

摘要

The pleiotropic cytokine tumor necrosis factor-alpha (TNF) has previously been shown to regulate both the proliferation and differentiation of normal rat mammary epithelial cells (MEC) in primary culture. TNF and TNF receptor expression were measured in isolated MEC and found to be independently and specifically regulated during mammary gland development. Using agonistic antibodies to either TNF receptor, the individual roles of each receptor were investigated in MEC in primary culture. The p55 TNF receptor was found to be the sole mediator of TNF-induced proliferation, while the two receptors were found to have opposing effects on functional differentiation. Further studies were undertaken to determine whether the post-receptor pathway of TNF action in MEC involved subsequent signaling via the EGF receptor. Using an inhibitor of the EGF receptor tyrosine kinase activity, PD158780, it was determined that the EGF receptor is not necessary for TNF action in normal MEC. Lastly, TNF and TNF receptor expression were measured in both DMBA- and NMU-induced mammary tumors, and the effects of TNF on the growth and morphogenesis and NMU-initiated and - transformed MEC in culture were determined.