INTERLEUKIN-1 ALPHA BLOCKS ESTRADIOL-STIMULATED GROWTH AND DOWN-REGULATES THE ESTROGEN-RECEPTOR IN MCF-7 BREAST-CANCER CELLS-INVITRO

We studied the effect of interleukin 1-alpha (IL-1-alpha) on estradiol stimulation of cell growth and estrogen receptor (ER) content in MCF-7 human breast cancer cells in vitro to determine if IL-1-alpha altered cellular estradiol responsiveness. We found that IL-1-alpha blocked estradiol-stimulated growth of these cells in a dose-dependent manner (complete antagonism at 1000 units/ml: day 7 mean growth = vehicle, 47.7-mu-g DNA; estradiol 10(-10) M, 95.1; IL-1-alpha/estradiol, 44.6) and at all concentrations of estradiol from 10(-8) to 10(-11) M. IL-1-alpha in combination with trans-hydroxytamoxifen further inhibited estradiol-stimulated growth (vehicle = 44.8-mu-g DNA, estradiol = 108.3, estradiol/trans-hydroxytamoxifen = 47.8, IL-1-alpha/estradiol/trans-hydroxytamoxifen = 3.0, P < 0.01). Inhibition with trans-hydroxytamoxifen was IL-1-alpha dose dependent (maximum = 97% at 1000 units/ml, P < 0.01) and estradiol dose dependent (reversible with 10(-8) M estradiol, maximum inhibition at 10(-10) M estradiol). Concomitantly, IL-1-alpha down-regulated ER concentration by 38.0-43.7% (P < 0.01) as measured by immunoreactivity or Scatchard analysis, respectively. This occurred as early as 3 h without a change in the K(d) (vehicle = 0.23 nM, IL-1-alpha = 0.24 nM), persisted for at least 48 h, was dose dependent (maximum, 43.7% at 1000 units/ml, P < 0.01), and was blocked by cycloheximide. IL-1-alpha, did not block estradiol stimulation of progesterone receptor content (vehicle = 221.9, IL-1-alpha = 238.9 fmol/mg protein) and did not block estradiol down-regulation of ER content. Furthermore, IL-1-alpha alone did not alter levels of ER mRNA and did not alter estradiol down-regulation of ER mRNA. These findings indicate that while IL-1-alpha antagonizes estradiol stimulation of growth and reduces ER content, its mechanism may involve other non-estrogen-regulated pathways.