Reducing side effect of estrogen based therapy by using Tissue-Selective Estrogen Complex

Mechanisms behind the Endometrial and Breast Safety of Tissue-Selective Estrogen Complex

Key Points

Highlight:

• A conjugated "estrogen/bazedoxifene" Tissue-Selective Estrogen Complex (TSEC) therapy has been developed to maximize the tissue-specific beneficial effects of selective estrogen-receptor modulators (SERMS) in uterus and breast tissues, while to minimize their side effects in other estrogen-target tissues such as the bone and brain.

Importance:

• Estrogen has essential physiological roles in specific target tissues. However, the aberrant regulation of estrogen receptor in certain diseases such as endometriosis has been targeted to minimise disease progression. Hence, estrogen receptor α (ERα) modulators are useful clinically but limited because of their side effects. The development of active tissue-specific ERα modulators is of significance.  

What's done here:

• This study analyzed the molecular functions of TSEC in endometrial and breast cells. Specifically, the transcriptional activity of these cells upon TSEC treatment was examined using ERα-estrogen response element (ERE)-DNA pull-down assays.

Data:

• ERα interacted with transcriptional repressors rather than coactivators upon TSEC treatment.
• TSEC treatment resulted in degradation of the uterine ERα protein in uterine tissue and breast cancer cells, but not in bone cells.
• In preclinical animal studies, TSEC suppressed estrogen-dependent progression of endometriosis.
• Endometrial and breast-specific effects of TSEC are associated with the selective recruitment of transcriptional repressors and degradation of the ERα protein.

Limitations:

• Studies are limited to in vitro cells and animal models; it is unclear whether the proposed mechanisms hold in clinical settings.

Lay Summary

The aberrant regulation of the ERα level in endometriosis and other estrogen-related diseases makes it a promising target for therapy. However, the standard beneficial roles of estrogen in specific target tissues, e.g., the bone, can be primarily affected by such treatment. To reduce these side effects, there has been continuous effort to develop tissue-specific modulators of ERα effectively to treat the estrogen-related disease progression while minimizing the side effects in certain tissues. This has led to the generation of selective estrogen-receptor modulators (SERMs), where they act as tissue-specific estrogen-receptor agonists in the bone, brain, cardiovascular system, vagina, and urogenital system and as estrogen-receptor antagonists in the breast, endometrium, pelvic floor, and in venous thrombosis. An example of SERM include tamoxifen for breast cancer, but chronic tamoxifen use may increase the risk of developing endometrial cancer. Later development of SERM discovered raloxifene, which reduced the incidence of invasive breast cancer in postmenopausal women with osteoporosis, and does not increase the risk of uterine cancers. The third-generation SERMs including bazedoxifene (BAZ) is for postmenopausal osteoporosis treatment without adverse effects on the breast and endometrium.

To further improve the tissue-specific effects of SERMs and minimize their side effects, tissue-selective estrogen complex (TSEC) was developed. The first-generation TSEC was a combination of BAZ and conjugated estrogen. Collective observations suggest that TSEC has an anti-estrogenic effect on breast cancer cells and prevents the development of endometrial hyperplasia in postmenopausal women. The goal of this article is to determine the molecular mechanisms of TSEC by understanding how it elicits the desired tissue-selective properties of SERMs and the beneficial effects of estrogen.

By studying ERα–estrogen response element (ERE)–DNA pull-down assays, the authors showed that upon TSEC treatment, ERα interacted primarily with transcriptional repressors rather than coactivators. Also, TSEC resulted in ERα protein degradation in uterine tissue and breast cancer cells, but not in bone cells, via interaction with the F-box protein 45 (FBXO45) E3 ubiquitin ligase. In preclinical animal studies, the effects of TSEC led to the suppression of ectopic lesion growth in mice with endometriosis. Collectively, this research suggests that TSEC treatment efficiently prevents ERα activity by selective mechanisms involving the recruitment of transcriptional repressors and FBXO45-mediated degradation of ERα in endometrial and breast cells. Understanding of such mechanisms can improve future design of TSEC.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/?term=26487511