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

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Mar 18

PMID 28306507

Citations 56

Authors

Joshua D Stender

Jerome C Nwachukwu

Irida Kastrati

Yohan Kim

Tobias Strid

Maayan Yakir

Sathish Srinivasan

Jason Nowak

Tina Izard

Erumbi S Rangarajan

Kathryn E Carlson

John A Katzenellenbogen

Xin-Qiu Yao

Barry J Grant

Hon S Leong

Chin-Yo Lin

Jonna Frasor

Kendall W Nettles

Christopher K Glass

Affiliations

Soon will be listed here.

Abstract

Human breast cancers that exhibit high proportions of immune cells and elevated levels of pro-inflammatory 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.

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