IL-1 Induces p62/SQSTM1 and Autophagy in ERα⁺/PR⁺ BCa Cell Lines Concomitant with ERα and PR Repression, Conferring an ERα⁻/PR⁻ BCa-Like Phenotype

Estrogen receptor α (ERα)ˡᵒʷ/⁻ tumors are associated with breast cancer (BCa) endocrine resistance, where ERα low tumors show a poor prognosis and a molecular profile similar to triple negative BCa tumors. Interleukin-1 (IL-1) downregulates ERα accumulation in BCa cell lines, yet the cells can remain viable. In kind, IL-1 and ERα show inverse accumulation in BCa patient tumors and IL-1 is implicated in BCa progression. IL-1 represses the androgen receptor hormone receptor in prostate cancer cells concomitant with the upregulation of the prosurvival, autophagy-related protein, Sequestome-1 (p62/SQSTM1; hereinafter, p62); and given their similar etiology, we hypothesized that IL-1 also upregulates p62 in BCa cells concomitant with hormone receptor repression. To test our hypothesis, BCa cell lines were exposed to conditioned medium from IL-1-secreting bone marrow stromal cells (BMSCs), IL-1, or IL-1 receptor antagonist. Cells were analyzed for the accumulation of ERα, progesterone receptor (PR), p62, or the autophagosome membrane protein, microtubule-associated protein 1 light chain 3 (LC3), and for p62-LC3 interaction. We found that IL-1 is sufficient to mediate BMSC-induced ERα and PR repression, p62 and autophagy upregulation, and p62-LC3 interaction in ERα⁺/PR⁺ BCa cell lines. However, IL-1 does not significantly elevate the high basal p62 accumulation or high basal autophagy in the ERα⁻/PR⁻ BCa cell lines. Thus, our observations imply that IL-1 confers a prosurvival ERα⁻/PR⁻ molecular phenotype in ERα⁺/PR⁺ BCa cells that may be dependent on p62 function and autophagy and may underlie endocrine resistance.

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Interleukin-1, SQSTM1 protein, human, Prostate—Cancer, Breast—Cancer, Estrogen—Receptors
National Institutes of Health, National Cancer Institute, Grant/Award Numbers:K01CA160602, R21CA17579
©2018 Wiley Periodicals, Inc.