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.
['Nawas|Afshan Fathima|AF|', 'Mistry|Ragini|R|', 'Narayanan|Shrinath|S|', 'Thomas-Jardin|Shayna Elizabeth|SE|', 'Ramachandran|Janani|J|', 'Ravichandran|Jananisree|J|', 'Neduvelil|Ebin|E|', 'Luangpanh|Krisha|K|', 'Delk|Nikki Ayanna|NA|http://orcid.org/0000-0001-9482-3830']
p62/SQSTM1 autophagy estrogen receptor α endocrine resistance interleukin-1