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

Nawas, Afshan F.; Mistry, Ragini M.; Narayanan, Shrinath; Thomas‐Jardin, Shayna E.; Ramachandran, Janani; Ravichandran, Jananisree; Neduvelil, Ebin; Luangpanh, Krisha; Delk, Nikkí A.

doi:10.1002/jcb.27340

Cited by 12 publications

(16 citation statements)

References 56 publications

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“…IL-1 conferred 350-gene signature is enriched in genes and pathways that promote BCa and PCa survival and progression. We have previously shown that HR low/-BCa 19 and PCa 18,42 cells are enriched when HR + cells are exposed to IL-1. Here, we sought to compare the gene expression pattern overlap between cells that lose hormone receptors in response to IL-1 to cells that are intrinsically HR -.…”

Section: Discussionmentioning

confidence: 95%

“…IL-1 is elevated in BCa and PCa tumors [8][9][10][11][12][13] and correlates with low or lost ERα or AR accumulation 10,[14][15][16][17] . We discovered that IL-1 downregulates ERα and AR levels in HR + BCa and PCa cell lines concomitant with the upregulation of pro-survival proteins that are basally high in HRcell lines 18,19 . Thus, IL-1 may select for and promote the evolution of treatment resistant cells, and our findings provide an opportunity to discover novel therapeutic targets for HR-independent BCa and PCa.…”

mentioning

confidence: 99%

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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

Nawas¹,

Kanchwala

Thomas‐Jardin

et al. 2019

Preprint

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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 blocks 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 HR -BCa cell lines. Finally, we performed Ingenuity Pathway Analysis (IPA) 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 HRcells. 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 treatment resistance. We also assessed HRcell line viability in response to the p62-targeting drug, verteporfin, and found that verteporfin is cytotoxic for HRcell 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. BACKGROUND: Breast (BCa) and prostate (PCa) cancer share similar etiology, where hormone receptors (HR) drive cancer cell survival 1,2 . Estrogen Receptor Alpha (ERα) promotes BCa tumor growth and Androgen Receptor (AR) promotes PCa tumor growth; thus, patients are treated with HR-targeting therapies. Unfortunately, patients can become treatment resistant due to loss of HR dependence. For example, ≥ 30% of patients that develop metastatic, castration-resistant PCa have AR-negative (AR -) tumors 3 and 15-30% of BCa patients that develop endocrine resistance have tumors with reduced or lost ERα accumulation 1,4 . In addition, at the time of

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

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

Nawas¹,

Kanchwala

Thomas‐Jardin

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…IL-1 is elevated in BCa and PCa tumors [8][9][10][11][12][13] and correlates with low or lost ERα or AR accumulation [10,[14][15][16][17]. We discovered that IL-1 downregulates ERα and AR levels in HR + BCa and PCa cell lines concomitant with the upregulation of pro-survival proteins that are basally high in HR − cell lines [18,19]. Thus, IL-1 may select for and promote the evolution of treatment-resistant cells, and our findings provide an opportunity to discover novel therapeutic targets for HR-independent BCa and PCa.…”

Section: Introductionmentioning

confidence: 90%

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

et al. 2020

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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.

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“…and PCa survival and progression. We have previously shown that HR low/-BCa 19 and PCa 18,62 cell populations are enriched when HR + cells are exposed to IL-1. Here, we sought to compare the gene expression pattern overlap between cells that lose hormone receptors in response to IL-1 to cells that are intrinsically HR -.…”

Section: Il-1 Conferred 350-gene Signature Is Enriched In Genes and Pmentioning

confidence: 97%

“…Identification of IL-1 conferred gene signature in hormone receptor positive BCa and PCa cell lines that mimic basal gene expression pattern in hormone receptor negative BCa andPCa cells. We previously found that IL-1 represses hormone receptors in ERa + /PR + BCa19 and AR + PCa18,62 cell lines concomitant with p62 upregulation, while ERa -/PR -BCa and AR -PCa cell lines intrinsically have high basal p62. This led us to speculate that IL-1 elicits similar changes in gene expression in hormone receptor positive (HR + ) BCa and PCa cells that mimic intrinsic gene expression patterns in hormone receptor negative (HR -) BCa and PCa cells.…”

mentioning

confidence: 95%

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

Nawas¹,

Kanchwala

Thomas‐Jardin³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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 blocks 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 HR- BCa 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.

show abstract

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

Cited by 12 publications

References 56 publications

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

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

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

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

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