An Innovative Method to Classify SERMs Based on the Dynamics of Estrogen Receptor Transcriptional Activity in Living Animals

Abstract

Using a mouse model engineered to measure estrogen receptor (ER) transcriptional activity in living organisms, we investigated the effect of long-term (21 d) hormone replacement on ER signaling by whole-body in vivo imaging. Estrogens and selective ER modulators were administered daily at doses equivalent to those used in humans as calculated by the allometric approach. As controls, ER activity was measured also in cycling and ovariectomized mice. The study demonstrated that ER-dependent transcriptional activity oscillated in time, and the frequency and amplitude of the transcription pulses was strictly associated with the target tissue and the estrogenic compound administered. Our results indicate that the spatiotemporal activity of selective ER modulators is predictive of their structure, demonstrating that the analysis of the effect of estrogenic compounds on a single surrogate marker of ER transcriptional activity is sufficient to classify families of compounds structurally and functionally related. For more than one century, the measure of drug structure-activity relationships has been based on mathematical equations describing the interaction of the drug with its biological receptor. The understanding of the multiplicity of biological responses induced by the drug-receptor interaction demonstrated the limits of current approach and the necessity to develop novel concepts for the quantitative analysis of drug action. Here, a systematic study of spatiotemporal effects is proposed as a measure of drug efficacy for the classification of pharmacologically active compounds. The application of this methodology is expected to simplify the identification of families of molecules functionally correlated and to speed up the process of drug discovery.

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

“…Conversely, BZA and TSEC were found to cluster with cycling mice, indicating the ability to reinstate oscillation more similar to that of cycling mice than that of ovx mice. This finding confirmed our previous findings in liver (17) as well as in other organs (18). Our measurements of liver FFA content revealed significantly higher levels of lipids in ovx mice treated with vehicle for 21 d (+84% vs. intact cycling mice); among the HRTs, only TSEC and BZA prevented liver FFA accumulation.…”

“…frequency of the oscillations induced by the treatments. We next evaluated the synchrony of the peaks of ER activity in liver and intestine, and analyzed the data obtained by agglomerative hierarchical clustering to identify the classes of compounds that most closely mimicked the ER oscillatory behavior characteristic of cycling mice (18). The results clearly indicated that ovariectomy changed the oscillatory pattern of ER significantly (as indicated by the Manhattan distance from the cycling mice), and that CE and RAL did not significantly improve the distance from the cycling controls (Fig.…”

“…ER oscillatory activity after SERM treatments was analyzed as described previously (18) and detailed in SI Methods. …”

The Effect of Bovine Cartilage on the Growth of Mouse B16F10 Melanoma Cells <i>in vitro</i> and <i>in vivo</i>

“…The oscillating effect is when a cycle of decrease and increase in physiological responses are seen to a given drug or substance after administration. The response doesn't remain low or high it represents as a transient cycle (Rando et al, 2010).…”

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…Bazedoxifene is currently prescribed for the prevention and treatment of osteoporosis, as bazedoxifene and raloxifene had similar impacts on bone mineral density and lipid profiles in a 24-month randomized clinical study (Miller et al . 2008) and on ER signaling in bone (Rando et al . 2010).…”