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Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer

Sustained HER2/HER3 signaling due to the overproduction of the HER3 ligand heregulin (HRG) is proposed as a key contributor to endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The molecular mechanisms linking HER2 transactivation by HRG-bound HER3 to the acquisition of a hormo...

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Autores principales: Papadimitropoulou, Adriana, Vellon, Luciano, Atlas, Ella, Steen, Travis Vander, Cuyàs, Elisabet, Verdura, Sara, Espinoza, Ingrid, Menendez, Javier A., Lupu, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589856/
https://www.ncbi.nlm.nih.gov/pubmed/33086721
http://dx.doi.org/10.3390/ijms21207737
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author Papadimitropoulou, Adriana
Vellon, Luciano
Atlas, Ella
Steen, Travis Vander
Cuyàs, Elisabet
Verdura, Sara
Espinoza, Ingrid
Menendez, Javier A.
Lupu, Ruth
author_facet Papadimitropoulou, Adriana
Vellon, Luciano
Atlas, Ella
Steen, Travis Vander
Cuyàs, Elisabet
Verdura, Sara
Espinoza, Ingrid
Menendez, Javier A.
Lupu, Ruth
author_sort Papadimitropoulou, Adriana
collection PubMed
description Sustained HER2/HER3 signaling due to the overproduction of the HER3 ligand heregulin (HRG) is proposed as a key contributor to endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The molecular mechanisms linking HER2 transactivation by HRG-bound HER3 to the acquisition of a hormone-independent phenotype in ER+ breast cancer is, however, largely unknown. Here, we explored the possibility that autocrine HRG signaling drives cytokine-related endocrine resistance in ER+ breast cancer cells. We used human cytokine antibody arrays to semi-quantitatively measure the expression level of 60 cytokines and growth factors in the extracellular milieu of MCF-7 cells engineered to overexpress full-length HRGβ2 (MCF-7/HRG cells). Interleukin-8 (IL-8), a chemokine closely linked to ER inaction, emerged as one the most differentially expressed cytokines. Cytokine profiling using structural deletion mutants lacking both the N-terminus and the cytoplasmic-transmembrane region of HRGβ2—which is not secreted and cannot transactivate HER2—or lacking a nuclear localization signal at the N-terminus—which cannot localize at the nucleus but is actively secreted and transactivates HER2—revealed that the HRG-driven activation of IL-8 expression in ER+ cells required HRG secretion and transactivation of HER2 but not HRG nuclear localization. The functional blockade of IL-8 with a specific antibody inversely regulated ERα-driven transcriptional activation in endocrine-sensitive MCF-7 cells and endocrine-resistant MCF-7/HRG cells. Overall, these findings suggest that IL-8 participates in the HRG-driven endocrine resistance program in ER+/HER2- breast cancer and might illuminate a potential clinical setting for IL8- or CXCR1/2-neutralizing antibodies.
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spelling pubmed-75898562020-10-29 Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer Papadimitropoulou, Adriana Vellon, Luciano Atlas, Ella Steen, Travis Vander Cuyàs, Elisabet Verdura, Sara Espinoza, Ingrid Menendez, Javier A. Lupu, Ruth Int J Mol Sci Brief Report Sustained HER2/HER3 signaling due to the overproduction of the HER3 ligand heregulin (HRG) is proposed as a key contributor to endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The molecular mechanisms linking HER2 transactivation by HRG-bound HER3 to the acquisition of a hormone-independent phenotype in ER+ breast cancer is, however, largely unknown. Here, we explored the possibility that autocrine HRG signaling drives cytokine-related endocrine resistance in ER+ breast cancer cells. We used human cytokine antibody arrays to semi-quantitatively measure the expression level of 60 cytokines and growth factors in the extracellular milieu of MCF-7 cells engineered to overexpress full-length HRGβ2 (MCF-7/HRG cells). Interleukin-8 (IL-8), a chemokine closely linked to ER inaction, emerged as one the most differentially expressed cytokines. Cytokine profiling using structural deletion mutants lacking both the N-terminus and the cytoplasmic-transmembrane region of HRGβ2—which is not secreted and cannot transactivate HER2—or lacking a nuclear localization signal at the N-terminus—which cannot localize at the nucleus but is actively secreted and transactivates HER2—revealed that the HRG-driven activation of IL-8 expression in ER+ cells required HRG secretion and transactivation of HER2 but not HRG nuclear localization. The functional blockade of IL-8 with a specific antibody inversely regulated ERα-driven transcriptional activation in endocrine-sensitive MCF-7 cells and endocrine-resistant MCF-7/HRG cells. Overall, these findings suggest that IL-8 participates in the HRG-driven endocrine resistance program in ER+/HER2- breast cancer and might illuminate a potential clinical setting for IL8- or CXCR1/2-neutralizing antibodies. MDPI 2020-10-19 /pmc/articles/PMC7589856/ /pubmed/33086721 http://dx.doi.org/10.3390/ijms21207737 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Papadimitropoulou, Adriana
Vellon, Luciano
Atlas, Ella
Steen, Travis Vander
Cuyàs, Elisabet
Verdura, Sara
Espinoza, Ingrid
Menendez, Javier A.
Lupu, Ruth
Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer
title Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer
title_full Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer
title_fullStr Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer
title_full_unstemmed Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer
title_short Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer
title_sort heregulin drives endocrine resistance by altering il-8 expression in er-positive breast cancer
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589856/
https://www.ncbi.nlm.nih.gov/pubmed/33086721
http://dx.doi.org/10.3390/ijms21207737
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