TUMOR-NECROSIS-FACTOR-ALPHA MODULATES ESTRADIOL RESPONSIVENESS OF MCF-7 BREAST-CANCER CELLS IN-VITRO

We studied the effect of tumour necrosis factor-alpha (TNF) on oestrad iol regulation of growth and metabolism of MCF-7 breast cancer cells t o determine whether TNF altered the oestradiol responsiveness of these cells. We found that TNF antagonized oestradiol stimulation of cell g rowth in a dose-dependent manner, with partial inhibition at l.0 U/ml and complete inhibition at 1000 U/ml. TNF inhibited cell cycle progres sion, increasing cells in the G(0)G(1) phase and blocking oestradiol-s timulated progression into the S phase. We examined the effect of TNF on three oestrogen-regulated proteins, the oestrogen receptor (ER), th e progesterone receptor (PR) and insulin-like growth factor-I (IGF-I). TNF down-regulated the ER and up-regulated the PR. Both of these proc esses were enhanced by the addition of oestradiol. The effects of TNF on the ER and PR were dose-dependent and occurred without a change in the Kd of the receptor. TNF did not change the respective steady-state mRNA levels. In addition, TNF did not alter secretion of IGF-I either ill the absence or presence of oestradiol, indicating that the effect s of TNF on oestrogen-regulated proteins is selective. These findings indicate all important interaction between the immune and endocrine sy stems. The cytokine TNF has a prominent effect on oestradiol stimulati on of MCF-7 cells, blocking its proliferative response and enhancing c ertain metabolic effects. These actions may be mediated in part throug h modulation of the ER, although other pathways appear to be involved.