MODULATION OF THE ESTROGEN-REGULATED PROTEINS CATHEPSIN-D AND PS2 BY OPIOID AGONISTS IN HORMONE-SENSITIVE BREAST-CANCER CELL-LINES (MCF7 AND T47D) - EVIDENCE FOR AN INTERACTION BETWEEN THE 2 SYSTEMS

In many cancer cell lines, including breast, prostate, lung, brain, he ad and neck, retina, and the gastrointestinal tract, opioids decrease cell proliferation in a dose-dependent and reversible manner. Opioid a nd/or other neuropeptide receptors mediate this decrease. We report th at only the steroid-hormone-sensitive cell lines MCF7 and T47D respond to opioid growth inhibition in a dose-dependent manner. Therefore, an interaction of the opioid and steroid receptor system might exist, as is the case with insulin. To investigate this interaction, we have as sayed two estrogen-inducible proteins (pS2 and the lysosomal enzyme ca thepsin D) in MCF7 and T47D cells. When cells were grown in the presen ce of FBS (in which case a minimal quantity of estrogens and/or opioid s is provided by the serum), we observed either no effect of etorphine or ethylketocyclazocine (EKC) or an increase of secretion and/or prod uction of pS2 and cathepsin D. However, when cells were cultured in ch arcoal-stripped serum and in the absence of phenol red, the effect of the two opioids is different: EKC decreased the production and/or secr etion of pS2 and cathepsin D, whereas etorphine increased their synthe sis and/or secretion. The differential effect of the two general opioi ds was attributed to their different receptor selectivity. Furthermore , the variations of the ratio of secreted/produced protein and the use of cycloheximide indicate that opioids selectively modify the regulat ory pathway of each protein discretely. In conclusion, through the int eraction with opioid and perhaps other membrane-receptor sites, opioid agonists modify in a dose-dependent manner the production and the sec retion of two estrogen-regulated proteins. Opioids may therefore distu rb hormonal signals mediated by the estrogen receptors. Hence, these c hemicals may have potential endocrine disrupting activities. J. Cell. Biochem. 71:416-428, 1998. (C) 1998 Wiley-Liss, Inc.