Identification of an IL‐1‐induced gene expression pattern in AR<sup>+</sup> PCa cells that mimics the molecular phenotype of AR<sup>−</sup> PCa cells

Thomas‐Jardin, Shayna E.; Kanchwala, Mohammed; Jacob, Joan; Merchant, Sana; Meade, Rachel Katherine; Gahnim, Nagham M.; Nawas, Afshan F.; Xing, Chao; Delk, Nikkí A.

doi:10.1002/pros.23504

Cited by 23 publications

(63 citation statements)

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“…We found that IL‐1 alone or in the HS‐5 CM milieu is sufficient to repress AR and induce p62 mRNA and protein accumulation in PCa cell lines. To determine if IL‐1 signaling is sufficient to mediate HS‐5 BMSC paracrine modulation of ERα, PR, p62, and/or autophagy in ERα + /PR + BCa cell lines, we blocked IL‐1 signaling in MCF7 and T47D cells with the IL‐1Ra.…”

Section: Resultsmentioning

confidence: 78%

“…We found that IL‐1 signaling downregulates AR in PCa cell lines concomitant with the induction of several prosurvival, progrowth pathways that may contribute to treatment resistance, such as p62 signaling . p62 is a multidomain scaffold protein that has been shown to be cytoprotective for multiple different cancer types and p62 mediates various prosurvival signaling cascades, including autophagy .…”

Section: Introductionmentioning

confidence: 95%

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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

Mistry

Narayanan

et al. 2018

J of Cellular Biochemistry

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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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Section: Resultsmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 95%

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

Mistry

Narayanan

et al. 2018

J of Cellular Biochemistry

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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.…”

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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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RELA is sufficient to mediate interleukin‐1 repression of androgen receptor expression and activity in an LNCaP disease progression model

et al. 2019

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Background: The Androgen Receptor (AR) nuclear transcription factor is a therapeutic target for prostate cancer (PCa). Unfortunately, patients can develop resistance to AR-targeted therapies and progress to lethal disease, underscoring the importance of understanding the molecular mechanisms that underlie treatment resistance. Inflammation is implicated in PCa initiation and progression and we have previously reported that the inflammatory cytokine, . CC-BY-NC-ND 4.

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Identification of an IL‐1‐induced gene expression pattern in AR⁺ PCa cells that mimics the molecular phenotype of AR⁻ PCa cells

Abstract: Our data supports that IL-1 reprograms AR PCa cells to mimic AR PCa gene expression patterns that favor AR-targeted treatment resistance and cell survival.

Cited by 23 publications

References 50 publications

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

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

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

RELA is sufficient to mediate interleukin‐1 repression of androgen receptor expression and activity in an LNCaP disease progression model

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Identification of an IL‐1‐induced gene expression pattern in AR+ PCa cells that mimics the molecular phenotype of AR− PCa cells

Abstract: Our data supports that IL-1 reprograms AR PCa cells to mimic AR PCa gene expression patterns that favor AR-targeted treatment resistance and cell survival.

Cited by 23 publications

References 50 publications

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

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

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

RELA is sufficient to mediate interleukin‐1 repression of androgen receptor expression and activity in an LNCaP disease progression model

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Identification of an IL‐1‐induced gene expression pattern in AR⁺ PCa cells that mimics the molecular phenotype of AR⁻ PCa cells

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

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

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