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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7589856 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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