We are studying the effect of interleukin-1 IL-1) on MCF-7 human breast cancer cell growth and metabolism. We found that IL-1 inhibits in a dose-dependent manner the growth of these cells. IL-1 acts to block cell growth in the G(0)G(1) phase of the cell cycle. We also found the IL-1 blocks estradiol stimulated growth of these cells. This is dose-dependent for IL-1 and occurs for all concentrations of estradiol from 10-8 to 10-11M. IL-1 acts synergistically with the estrogen antagonist hydroxytamoxifen to further inhibit cell growth; this synergism with hydroxytamoxifen is also dose-dependent for IL01. IL-1 has been found to down-regulate the estrogen receptor (ER) in these cells by 38.0-44.0%. Down-regulation is demonstrated by both Scatchard analysis and enzyme immunoassay. Down-regulation occurs by 12 hours and persists through 48 hours of exposure, is dose-dependent, and occurs without a change in the receptor affinity constant (Kd) Down-regulation is blocked by cycloheximide, and thus requires continuous protein synthesis. IL-1 does not, however, alter expression of ER MRNA and therefore IL-1 is acting at the post-transcriptional level to down-regulate the ER. IL-1 did not block estradiol stimulation of progesterone (PgR) synthesis as determined by Scatchard analysis of EIA, and did not alter resting PgR levels. IL-1 also did not block estradiol down-regulation of the ER or ER MRNA. The effect of IL-1 on secretion of insulin-like growth factor was examined. IL-1 decreased resting levels of IGF, however, did not block estradiol stimulation of IGF secretion, further indicating that IL-1 selectively alters the estrogen responsiveness of these cells. We are currently studying the effect of IL-1 on growth and metabolism of MCF-7 cells in vivo in nude mice, as well as the effect of IL-1 on TGF-beta growth factor secretion, protooncogene erbB expression and EGF receptor expression, and modultion of estradiol regulation of cell cycle phase distribution.
