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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
Nikki Delk
University of Texas at Dallas
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9482-3830
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Cancer.
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.
Keywords
Interleukin-1, breast cancer, prostate cancer, p62/SQSTM1, estrogen receptor, androgen receptor
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On 06 Jan, 2020
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On 30 Dec, 2019
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Editorial decision: Minor revision
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Received 19 Dec, 2019
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On 18 Dec, 2019
Reviewer #2 agreed
On 03 Dec, 2019
Reviewers invited
Invitations sent on 25 Nov, 2019
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On 25 Nov, 2019
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On 13 Nov, 2019
Editor invited
On 13 Nov, 2019
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On 13 Nov, 2019
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Editorial decision: Major revision
On 14 Oct, 2019
Review #2 received
Received 13 Oct, 2019
Review #1 received
Received 03 Oct, 2019
Reviewer #3 agreed
On 22 Sep, 2019
Reviewer #2 agreed
On 20 Sep, 2019
Reviewers invited
Invitations sent on 19 Sep, 2019
Reviewer #1 agreed
On 19 Sep, 2019
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This preprint is under consideration at BMC Cancer. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
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
Nikki Delk
University of Texas at Dallas
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9482-3830
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 4
Posted 13 Jan, 2020
Published
On 20 Jan, 2020
No community comments so far
Submission checks complete
On 10 Jan, 2020
Editorial decision: Accept
On 10 Jan, 2020
No comments provided
Editorial decision: Minor revision
On 06 Jan, 2020
Editor assigned
On 30 Dec, 2019
Editor invited
On 29 Dec, 2019
Submission checks complete
On 27 Dec, 2019
No comments provided
Review #3 received
Received 23 Dec, 2019
Editorial decision: Minor revision
On 23 Dec, 2019
Review #1 received
Received 19 Dec, 2019
Review #2 received
Received 19 Dec, 2019
Reviewer #3 agreed
On 18 Dec, 2019
Reviewer #2 agreed
On 03 Dec, 2019
Reviewers invited
Invitations sent on 25 Nov, 2019
Reviewer #1 agreed
On 25 Nov, 2019
Submission checks complete
On 13 Nov, 2019
Editor invited
On 13 Nov, 2019
Editor assigned
On 13 Nov, 2019
No comments provided
Editorial decision: Major revision
On 14 Oct, 2019
Review #2 received
Received 13 Oct, 2019
Review #1 received
Received 03 Oct, 2019
Reviewer #3 agreed
On 22 Sep, 2019
Reviewer #2 agreed
On 20 Sep, 2019
Reviewers invited
Invitations sent on 19 Sep, 2019
Reviewer #1 agreed
On 19 Sep, 2019
Submission checks complete
On 19 Sep, 2019
Editor assigned
On 19 Sep, 2019
Editor invited
On 18 Sep, 2019
First submitted
On 05 Sep, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Cancer.
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6