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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doaj-864add846ff84293b683f04f37da82a42020-11-25T02:00:21ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-01217737773710.3390/ijms21207737Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast CancerAdriana Papadimitropoulou0Luciano Vellon1Ella Atlas2Travis Vander Steen3Elisabet Cuyàs4Sara Verdura5Ingrid Espinoza6Javier A. Menendez7Ruth Lupu8Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, GreeceStem Cells Laboratory, Institute of Biology and Experimental Medicine (IBYME-CONICET), Buenos Aires C1428ADN, ArgentinaEnvironmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9 CanadaDivision of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USAProgram Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, SpainProgram Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, SpainDepartment of Preventive Medicine, John D. Bower School of Population Health, University of Mississippi Medical Center, Jackson, MS 39216, USAProgram Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, SpainDepartment of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa ON K1N 6N5, CanadaSustained 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 <i>N</i>-terminus and the cytoplasmic-transmembrane region of HRGβ2—which is not secreted and cannot transactivate HER2—or lacking a nuclear localization signal at the <i>N</i>-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.https://www.mdpi.com/1422-0067/21/20/7737cytokinesIL-8tamoxifenautocrineluminal |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Adriana Papadimitropoulou Luciano Vellon Ella Atlas Travis Vander Steen Elisabet Cuyàs Sara Verdura Ingrid Espinoza Javier A. Menendez Ruth Lupu |
spellingShingle |
Adriana Papadimitropoulou Luciano Vellon Ella Atlas Travis Vander Steen Elisabet Cuyàs Sara Verdura Ingrid Espinoza Javier A. Menendez Ruth Lupu Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer International Journal of Molecular Sciences cytokines IL-8 tamoxifen autocrine luminal |
author_facet |
Adriana Papadimitropoulou Luciano Vellon Ella Atlas Travis Vander Steen Elisabet Cuyàs Sara Verdura Ingrid Espinoza Javier A. Menendez Ruth Lupu |
author_sort |
Adriana Papadimitropoulou |
title |
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_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_sort |
heregulin drives endocrine resistance by altering il-8 expression in er-positive breast cancer |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-10-01 |
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 <i>N</i>-terminus and the cytoplasmic-transmembrane region of HRGβ2—which is not secreted and cannot transactivate HER2—or lacking a nuclear localization signal at the <i>N</i>-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. |
topic |
cytokines IL-8 tamoxifen autocrine luminal |
url |
https://www.mdpi.com/1422-0067/21/20/7737 |
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