Interplay between Estradiol and Prolactin in the Regulation of Steroid Hormone Receptor Levels, Nature, and Functionality in Normal Mouse Mammary Tissue*

Under different experimental conditions, normal mouse mammary tissue can be shown to contain molecular species of cytoplasmic estrogen receptors which differ in their physicochemical properties and kinetic behavior with respect to estradiol binding. The relative capabilities of PRL and estradiol to effect molecular interconversion of these receptor forms have been examined. Chronic administration of estradiol to a mature virgin mouse increases nuclear receptor levels 5-fold and converts cytoplasmic receptors from a 4S to an 8S form. PRL has an even greater augmentative effect on cellular receptor content, also causing 4S to 8S conversion, but is much less effective than estradiol in elevating nuclear receptor levels. CB-154, which blocks PRL production, totally inhibits estrogen promotion of specific binding activity, while partially permitting 8S cytoplasmic receptor formation. Short term administration of estradiol to a mouse in late pregnancy (all cytosol receptor in the 8S form) causes a cytosol to nuclear shift in receptor distribution without an increase in receptor number. In the same animal model, PRL alone greatly elevates cytoplasmic 8S binding, with no appreciable effect on nuclear levels. Simultaneous administration of PRL and estradiol results in the same receptor stimulation as that seen with PRL alone, but in this instance, the nucleus is the site of increased binding. Progesterone receptor activity in the virgin mouse is not increased by PRL as it is by estradiol. The combined action of estradiol plus PRL, however, causes a striking enhancement of cytosol receptor binding without the expected concomitant extent of increase in nuclear binding. In late pregnancy, moreover, PRL alone results in marked diminution of nuclear receptor binding. Mammary tissue from BALB/c mice is less responsive to the receptor-related actions of PRL than is tissue from C3H+ mice. The 8S receptor form differs from the 4S form in its steroidal specificity in a manner suggesting greater tolerance of structural deviation from estradiol. The 8S species and its heat-activated 5S derivative manifest greater affinity for DNA than do the corresponding 4S complex and its heat-transformed 5S species. The results indicate that the hormonal environment of mouse mammary tissue dictates the physicochemical nature and binding properties of estrogen receptors, which, in turn, results in alterations in intracellular distribution and functionality.