Rüdiger K. Wagner

Prognostic significance of estrogen receptor status in breast cancer in relation to tumor stage, axillary node metastasis, and histopathologic grading

The value of estrogen receptor (ER) measurements for predicting recurrence and survival rates in primary breast cancer was examined in 121 women who were followed from 5 to 12 years after mastectomy with a median follow‐up of 64 months. The prognostic significance of the ER status was evaluated independently and in association with tumor stage, axillary node metastasis, and histopathologic grade. The independent evaluation demonstrated no statistically significant difference in prognosis between women with ER‐negative and ER‐positive cancers, although the latter group tended to have a longer time to recurrence and longer survival. Multivariate analysis of the data by Coxs proportional hazard regression techniques revealed a synergistic effect of ER status on the risk associated with axillary node metastasis. Patients with nodal metastasis were at 2.8 times the risk of recurrence compared to patients without metastasis. For women with nodal metastasis whose primary cancer was ER‐negative, this risk increased to 4.6 times compared to women without metastasis and ER‐positive tumors (P = 0.0003). The risk of cancer‐related death was 5.6 times more likely for poorly differentiated tumors than for highly differentiated tumors. Patients with poorly differentiated ER‐negative tumors were at an even higher risk (7.0) of dying than women with highly differentiated ER‐positive carcinomas (P = 0.009). In conjunction with tumor stage, axillary node metastasis and histopathologic grade ER determination is useful for identifying subpopulations at increased risk of tumor recurrence or mortality.

The histopathological evaluation of human breast cancers in correlation with estrogen receptor values

A detailed histopathological review of 140 primary breast cancers analyzed for estrogen receptor protein (ERP) was carried out and a variety of morphological features correlated with ERP results. ERP in cytosols was incubated with [3H]estradiol in the presence and absence of cold estradiol and assayed by agargel electrophoresis. Tumors binding > 10 fmol estradiol/mg tissue protein were classified as receptor‐positive. Seventy‐seven percent of the 116 infiltrating duct carcinomas were ERP‐positive. The well‐differentiated tumors of this group had a higher incidence of ERP‐positivity than the poorly differentiated ones. The ten predominantly or exclusively intraductal carcinomas and the seven medullary tumors were less frequently positive than the main group of infiltrating ductal cancers. The three colloid, two tubular, and two lobular carcinomas in this series were all ERP‐positive. When receptor measurements are evaluated, consideration should be given to the degree of differentiation and the histological type of tumor, in addition to other factors known to influence receptor levels such as menopausal status and seasonal variation.

Ovarian-independent fluctuations of estradiol receptor levels in mammalian tissues.

Three types of periodic fluctuation in tissue concentrations of estradiol receptor protein have been observed. A seasonal variation is described in the uteri of 12-16-week-old calves and of ovariectomized pigs, and in mammary tumor tissue obtained from postmenopausal women. A circadian rhythm has been demonstrated in uteri of ovariectomized rats. An irregular periodic fluctuation has been found in uteri of ovariectomized and of ovariectomized/hypophysectomized rats, with the period varying from 9 to 15 days. These observations establish that a substantial turnover of receptor occurs in the absence of hormone and that normal baseline values of receptor concentration do not exist.

Activation of transcription-regulating proteins by steroids☆

Abstract The intracellular proteins, which bind steriod hormones with high affinity and specificity have been generally considered as instruments of hormone action. A reversal of assignments might seem a merely semantic exercise, but is indeed in better agreement with experimental evidence identifying ‘receptors’ as transcription-regulating proteins. The series of events in the presence of hormone are: 1. attachment of the steroid to the ‘receptor’ which undergoes a major conformational change when ‘enveloping’ the steroid, 2. dimerization to steroid-receptor: steroid-receptor 3. translocation of the dimer into the nucleus, 4. enhancement of transcription. One product of the latter is ‘receptor’ mRNA, the translation of which initiates within 60–90 min after pulse-administration of steroid. In the absence of hormone, ‘receptor translocation’, degradation and biosynthesis continue to proceed but at a much slower rate. Although these results have been primarily obtained with the estradiol-‘receptor’ system, all other systems seem to follow the same pattern. The molecular mechanism by which enhancement of transcription is achieved is as yet unknown. Its specificity must be quite particular since several steroid-‘receptor‘ systems occur simultaneously within the same cell.

MECHANISMS INVOLVED IN THE REGULATION OF STEROID RECEPTOR LEVELS

Abstract The turnover of steroid receptors comprises: synthesis in the cytoplasm, translocation into the cell nucleus and degradation at a still unknown site. From studies on the oestradiol/receptor system, the following conclusions can be drawn. 1. The in-vivo uptake of oestradiol by target cell nuclei is receptordependent. Steroid and receptor are translocated from the cytoplasm in a 1:1 ratio. A recycling of receptor is undetectable after pulse administration of oestradiol. Receptor replenishment in the cytoplasm is accomplished by synthesis. 2. The nuclear uptake of receptor-in contrast-proceeds also in the absence of oestradiol. Both forms of receptor, monomer and “activated” dimer are present in oestrogen-free nuclei. 3. Oestradiol enhances the “nucleotropy” and the turnover rate of receptor. 4. Oestrogenicity and antioestrogenicity are apparently linked to effects exerted on the “nucleotropy” of receptor and its ability to interact with the relevant nuclear structures.

Differentiation between steroid hormone receptors CBG and SHBG in human target organ extracts by a single-step assay.

The steroid complexes of (plasma) corticosteroid-binding globulin can be distinguished from intracellular steroid-receptor complexes by agar electrophoresis at low temperature in neuraminidase-treated tissue extracts. With this method, the presence of progesterone receptor has been demonstrated in heavily plasma-protein-contaminated human uterus cytosol, but not in human mammary carcinoma extracts. SHBG and basic receptors for estradiol and dihydrotestosterone in human uterus cytosol could also be assayed simultaneously.

Binding of Steroids by Tissue Proteins Steroid hormone “receptors”

Publisher Summary This chapter discusses the binding of steroids by tissue proteins steroid hormone “receptors”. Estrogens are among the biologically active substances that act at the cellular level in low concentrations. They have been compared earlier with cardiac glycosides for which pharmacologists proposed a sort of hit and run mechanism of action, because the minute amounts present could not be detected with the techniques available. With the advent of radioactive compounds of high specific activity, this concept had to be revised. The experiments of Jensen and Jacobson extended and confirmed by numerous laboratories, leave no doubt that estradiol is selectively accumulated and retained by the target cells.

An evaluation of the agargel electrophoretic method for the analysis of specific steroid binding proteins

Abstract This paper presents data on the reproducibility of the agargel electrophoretic method for the analysis of specific steroid binding proteins, together with an evaluation of the auxiliary techniques required to produce a suitable assay sample. We find for intra-assay variability a coefficient of variation of approximately 3%, while for the interassay variability the value is approximately 7%. The method is also shown capable of assessing and correcting for the dissociation of the steroid-protein complexes during analysis. In view of the current preoccupation with the clinical utility of receptor assays, we feel that similar data should be made available for the other commonly used receptor assays.