Current and Future Development of Estrogen Receptor Ligands: Applications in Estrogen-Related Cancers

Abstract

17β;-Estradiol (E2), via its cognate receptors (ERs), regulates several aspects of human physiology including development, reproduction and tissue homeostasis. Consequently, E2 could also be implicated in the development or progression of several pathologies, including cancer. Two different ER subtypes are present in mammals (ERβ and ERβ), which display specific roles in E2-related cancers, different tissue distribution, and multiple action mechanisms (i.e., genomic and extranuclear mechanisms). Here, the complex pattern of the relative contribution of each ER subtype in the E2- dependent cancers has been summarized by taking into consideration the molecular events which occur both in the nucleus and in extranuclear compartments. In the second part of this paper, we reviewed the current literature available on the drug-targeting of the ERs, as well as the recent literature and patents describing new and upcoming molecules. These new molecules will probably greatly improve the repertoire of anti-hormonal therapeutic strategies. However, further new drug design programs, which should include all molecular mechanisms at the basis of ER biology, are needed to expand the anti-ER treatments in new and more efficient therapeutic directions. This review also outlines relevant patents.

Sustained proliferation in cancer: Mechanisms and novel therapeutic targets

“…Membrane ERα expressing breast cancers also show a strong positive correlation with phosphorylated Akt and HER2 overexpression [280], the latter of which is characteristic of ‘invasive carcinoma’ [281]. In addition, ERα plasma membrane localization and its interactions with IGFR1 and EGFR/ErbB2 may be one of the mechanisms underlying the development of drug resistance in breast cancer cells [282,283]. Androgen independent prostate cancer is also mediated by IGFR-1/IGF-1 [284] and elevated EGFR/ErbB-2 [285], combined with downstream Akt [286,287] and Janus kinase (JAK)/STAT [288] and MAPK signaling.…”

“…Nuclear localization of ERs [294,295] is now considered to have prognostic significance. Very few drugs for breast cancer have been shown to target ERs extranuclear mechanisms [283]. …”

“…Flavonoids inhibit hormone related cancers by modulating the activities of sex steroid hormone receptors [283,363,364]. Upon receptor binding, flavonoids reduce ERα association with the plasma membrane, impair ERα dependent proliferative signaling cascades, and promote apoptosis through the activation of ERα-mediated p38/MAPK [365-367].…”

Tyrosine Phosphatase Shp2 Mediates the Estrogen Biological Action in Breast Cancer via Interaction with the Estrogen Extranuclear Receptor

“…The extranuclear ER pathway is involved in several crucial cellular functions such as cell proliferation, migration, secretion, and apoptosis [3], [4]. Knowledge on these novel estrogen actions is now significantly broadening our understanding of breast carcinogenesis, particularly regarding metastasis and drug resistance [5], [6].…”

Targeting Estrogen Receptor-β for the Prevention of Nonmelanoma Skin Cancer

“…The finding that activation of ERβ with ERB-041 inhibited UVB-induced skin tumorigenesis by interfering with proinflammatory signaling is consistent with other studies. The mechanism underlying this effect was not definitively shown in this study but could be due to ERβ interfering with NF-κB-dependent signaling as suggested by others (19). This type of interaction has also been noted with other nuclear receptors such as peroxisome proliferator-activated receptors (20).…”