DIFFERENT ESTROGEN-RECEPTOR STRUCTURAL DOMAINS ARE REQUIRED FOR ESTROGEN-DEPENDENT AND TAMOXIFEN-DEPENDENT ANTIPROLIFERATIVE ACTIVITY IN HUMAN MAMMARY EPITHELIAL-CELLS EXPRESSING AN EXOGENOUS ESTROGEN-RECEPTOR
Da. Zajchowski et al., DIFFERENT ESTROGEN-RECEPTOR STRUCTURAL DOMAINS ARE REQUIRED FOR ESTROGEN-DEPENDENT AND TAMOXIFEN-DEPENDENT ANTIPROLIFERATIVE ACTIVITY IN HUMAN MAMMARY EPITHELIAL-CELLS EXPRESSING AN EXOGENOUS ESTROGEN-RECEPTOR, Journal of steroid biochemistry and molecular biology, 62(5-6), 1997, pp. 373-383
Estrogen (E) inhibits the growth of both non-tumorigenic, immortal hum
an mammary epithelial cells (HMEC) and breast cancer cells which stabl
y express exogenous estrogen receptors (ER). The anti-estrogenic compo
unds 4-hydroxy-tamoxifen (HT) and ICI 164384 (ICI) have different effe
cts on the growth of the ER-transfectants. HT is a potent growth inhib
itor, while ICI has no effect by itself but is able to block the anti-
proliferative effects of E and HT. In order to elucidate the mechanism
by which E or HT-bound ER inhibit cell growth, we have evaluated the
effects of these compounds on the growth of HMEC stably expressing ER
with mutations or deletions in the N-terminal A/B domain, the DNA-bind
ing domain (DBD), and the C-terminal ligand-binding domain. These stud
ies revealed that E and HT require different structural domains of the
ER for their anti-proliferative activities. The N-terminal APS domain
is required for HT-, but not E-dependent growth inhibition. The DNA-b
inding domain of the ER is not essential for HT-mediated anti-prolifer
ative effects, but is important for E-dependent activity. The effect o
f ER mutations on the ligand-inducible expression of the endogenous pr
ogesterone receptor (PR) and pS2 genes was also evaluated. Neither gen
e was induced in the cells containing the ER mutated in the DBD, even
though cell growth was inhibited. These results suggest that E and HT
use different pathways to elicit their anti-proliferative effects and
that this occurs via modulation of genes that are controlled by mechan
isms different from those important for activation of the PR and pS2 g
enes. (C) 1997 Elsevier Science Ltd. All rights reserved.