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oai:recercat.cat:10256/207912024-06-18T12:41:40Zcom_2072_452955com_2072_2054col_2072_453079

Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer Papadimitropoulou, Adriana Vellon, Luciano Atlas, Ella Van der Steen, Travis Cuyàs, Elisabet Verdura, Sara Espinoza, Ingrid Menéndez Menéndez, Javier Abel Lupu, Ruth Citocines Cytokines Mama -- Càncer -- Tractament Breast -- Cancer -- Treatment Mama -- Càncer -- Aspectes moleculars Breast -- Cancer -- Molecular aspects Estrògens -- Receptors Estrogen -- Receptors 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 2020-10-19 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion peer-reviewed http://hdl.handle.net/10256/20791 http://hdl.handle.net/10256/20791 eng info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms21207737 info:eu-repo/semantics/altIdentifier/issn/1422-0067 info:eu-repo/semantics/altIdentifier/eissn/1422-0067 Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf MDPI (Multidisciplinary Digital Publishing Institute) International Journal of Molecular Sciences, 2020, vol. 21, núm. 20, p. 7737 Articles publicats (IdIBGi) Papadimitropoulou, Adriana Vellon, Luciano Atlas, Ella Steen, Travis Vander Cuyàs, Elisabet Verdura, Sara Espinoza, Ingrid Menéndez Menéndez, Javier Abel Lupu, Ruth 2020 Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer International Journal of Molecular Sciences 21 20 7737