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

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 ER alpha-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ER alpha and endocrine resistance is dependent on phosphorylation of ER alpha at S305 in the hinge domain. Phosphorylation of S305 by IKK beta establishes an ER alpha cistrome that substantially overlaps with the estradiol (E2)-dependent ER alpha cistrome. Structural analyses suggest that S305-P forms a charge-linked bridge with the C-terminal F domain of ER alpha that enables inter-domain communication and constitutive activity from the N-terminal coactivator-binding site, revealing the structural basis of endocrine resistance. ER alpha therefore functions as a transcriptional effector of cytokine-induced IKK beta signaling, suggesting a mechanism through which the tumor microenvironment controls tumor progression and endocrine resistance.