IL-1-conferred gene expression pattern in ERα(+) BCa and AR(+) PCa cells is intrinsic to ERα(−) BCa and AR(−) PCa cells and promotes cell survival

BACKGROUND: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Thus, BCa and PCa patients are given therapies that reduce hormone levels or directly block HR activity; but most patients eventually develop treatment resistance. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERα and AR mRNA in HR-positive (HR(+)) BCa and PCa cell lines, yet the cells can remain viable. Additionally, we identified pro-survival proteins and processes upregulated by IL-1 in HR(+) BCa and PCa cells, that are basally high in HR(−) BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR(+) BCa and PCa cells that mimics conserved basal gene expression patterns in HR(−) BCa and PCa cells to promote HR-independent survival and tumorigenicity. METHODS: We performed RNA sequencing (RNA-seq) for HR(+) BCa and PCa cell lines exposed to IL-1 and for untreated HR(−) BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in the BCa and PCa cell lines. Finally, we performed Ingenuity Pathway Analysis (IPA) and used the gene ontology web-based tool, GOrilla, to identify signaling pathways encoded by our RNA-seq data set. RESULTS: We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR(+) cells that are, respectively, basally high or low in HR(−) cells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR(−) BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in HR-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired hormone receptor independence and treatment resistance. We also assessed HR(−) cell line viability in response to the p62-targeting drug, verteporfin, and found that verteporfin is cytotoxic for HR(−) cell lines. CONCLUSIONS: Our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic HR-independent BCa and PCa.