Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells

Abstract

Summary Human breast cancers that exhibit high proportions of immune cells and elevated levels of proinflammatory cytokines predict poor prognosis. Here, we demonstrate that treatment of human MCF-7 breast cancer cells with pro-inflammatory cytokines results in ERα-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ERα and endocrine resistance is dependent on phosphorylation of ERα at S305 in the hinge domain. Phosphorylation of S305 by IKKβ establishes an ERα cistrome that substantially overlaps with the estradiol (E2)-dependent ERα cistrome. Structural analyses suggest that S305-P forms a charge-linked bridge with the C-terminal F domain of ERα that enables inter-domain communication and constitutive activity from the N-terminal coactivator-binding site, revealing the structural basis of endocrine resistance. ERα therefore functions as a transcriptional effector of cytokine-induced IKKβ signaling, suggesting a mechanism through which the tumor microenvironment controls tumor progression and endocrine resistance.

BRCA1-mimetic compound NSC35446.HCl inhibits IKKB expression by reducing estrogen receptor-α occupancy in the IKKB promoter and inhibits NF-κB activity in antiestrogen-resistant human breast cancer cells

“…A recent study indicates that pro-inflammatory cytokines can induce antiestrogen resistance in MCF-7 cells that is dependent on phosphorylation of ERα at S305 [48]. This phosphorylation, which causes a conformational change in ERα that induces antiestrogen resistance in MCF-7 cells is mediated by IKKB.…”

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

“…It was Frasor et al who showed that treatment with TNFα and estradiol regulated a set of genes that are clinically relevant because they can distinguish patients with poor response to endocrine treatment (109). In fact, both molecules act together to promote survival of breast cancer cells and progression onto a more aggressive phenotype (110). In this regard, by using global run-on coupled with deep sequencing (GRO-seq) in MCF-7 breast cancer cells, it was demonstrated that TNFα was responsible for exposing latent estrogen receptor binding sites to which estradiol could bind to regulate gene expression.…”

The estrogen–macrophage interplay in the homeostasis of the female reproductive tract

“…Estrogen receptor activity can be switched on or off by other endogenous molecules. Receptor activation may be triggered by intracellular kinases that are activated by diverse signals, including inflammatory cytokines, and induce modifications in the ERα conformation resulting in receptor-mediated genomic (Stellato et al, 2016) (Stender et al, 2017). Moreover, progesterone is known to oppose estrogen actions in the uterus and vagina through the differentiation from proliferative to secretory endometrial cells, production of less potent estrogens and formation of vaginal mucus that hinders sperm survival (Patel et al, 2015).…”