Estrogen Receptor Complex to Trigger or Delay Estrogen-Induced Apoptosis in Long-Term Estrogen Deprived Breast Cancer.

Philipp Y Maximov,V Craig Jordan,Balkees Abderrahman,Ping Fan,Ramona Curpan

doi:10.3389/fendo.2022.869562

Abstract

Antiestrogen therapy of breast cancer has been a “gold standard” of treatment of estrogen receptor (ER)-positive breast cancer for decades. Resistance to antiestrogen therapy may develop, however, a vulnerability in long-term estrogen deprived (LTED) breast cancer cells was discovered. LTED breast cancer cells may undergo estrogen-induced apoptosis within a week of treatment with estrogen in vitro. This phenomenon has been also validated in vivo and in the clinic. The molecular ER-mediated mechanism of action of estrogen-induced apoptosis was deciphered, however, the relationship between the structure of estrogenic ligands and the activity of the ER in LTED breast cancer cells remained a mystery until recently. In this review we provide an overview of the structure-activity relationship of various estrogens with different chemical structures and the modulation of estrogen-induced apoptosis in LTED breast cancer cells resistant to antihormone therapy. We provide analysis of evidence gathered over more than a decade of structure-activity relationship studies by our group on the role of the change in the conformation of the estrogen receptor and the biological activities of different classes of estrogens and the receptor as well in LTED breast cancer.

Highlights

Breast cancer has the highest incidence in women with 252,710 new cases and 40,610 deaths in 2017 [1]
Despite the fact that Z2OHTPE is able to activate the transcription of estrogen regulated genes like TFF1 and GREB1 as well as E2 and recruit estrogen receptor (ER) protein to their promoter regions to E2, as demonstrated by Chromatin Immunoprecipitation assays (ChIP) assays, the compound still was lagging in the recruitment of SRC3
Molecular dynamic simulations revealed that, TTC-352 produces a more stable agonist conformation of the ER ligand-binding domain (LBD) and positioning of helix 12 with low volatility when compared to bisphenol TPE (BPTPE), which can explain the compound’s full agonist activity in the long-term estrogen deprived (LTED) breast cancer cells [87]

Summary

Introduction

Breast cancer has the highest incidence in women with 252,710 new cases and 40,610 deaths in 2017 [1]. It was demonstrated in previously described ER-negative breast cancer cells stably transfected with DNA constructs expressing wild-type or mutant ER that planar estrogens, such as E2 and DES (Figure 3) (which has been used on Sir Alexander Haddow’s clinical trials in the 1940’s), activated the ER regardless of the Asp351 mutational status.

Results

Conclusion