CHARACTERIZATION OF A TWO-COMPONENT ESTROGEN-RECEPTOR COMPLEX IN THE MTW-9B TRANSPLANTABLE RAT MAMMARY TUMOR

The estrogen-receptor (ER) positive MTW-9B rat mammary tumor demonstrates a dissociation between estrogen (E(,2))-induced tumor growth and progesterone receptor (PgR) regulation. Finding potential explanations for this selective action of the ER-complex has been the focus of this study. The first objective was to determine whether the tumor has a two-component binding system for E(,2). Two E(,2)-binders were characterized; one conforms to the classical ER (type I) with high affinity (K(,d)) and limited binding capacity (B(,max)) and the second (type II) demonstrates a high number of sites and low, but specific, affinity for E(,2). The type I and II binders sediment at 10 and 4S on sucrose gradient analysis (SGA) and focus at isoelectric points of 6.62 (+OR-) 0.10 and 7.89 (+OR-) 0.06 on isoelectric focusing analysis, respectively.; The next objective was to determine whether the two binders were hormonally regulated. Transplantation of the tumor into intact and castrated male and femal W/Fu rats demonstrated that the K(,d) for both binders was significantly increased in intact males relative to females. No effect of ovariectomy was demonstrated for either binder while the B(,max) for the type I was significantly decreased in intact males relative to remaining groups. Tumor growth was unaffected by hormone-depletion, but was retarded in intact males relative to intact females. SGA revealed that the type II/type I ratio was significantly increased in intact males, indicating that this increase may be correlated with decreased tumor growth.; An additional objective was to determine whether the type II-binder is associated with type I containing cells. In vivo selection of a MTW-9B tumor-variant containing only the type II was accomplished after successive transplants into intact males; type I was absent and was not induced by estrogen. These data suggest that the type I may not be a precursor to the type II-binder. The observation of PgR synthesis in the absence of estrogen and/or the type I suggests that PgR synthesis is constitutive. Additional preliminary experiments suggest translocation and DNA-binding ability of the type II in this variant, in contrast to an apparent lack of translocation of this binder in the parent tumor.