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 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. Fil: Papadimitropoulou, Adriana. Academy of Athens; Grecia Fil: Vellón, Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Atlas, Ella. University of Ottawa; Canadá Fil: Steen, Travis Vander. Mayo Clinic; Estados Unidos Fil: Cuyàs, Elisabet. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España. Institut Català d'Oncologia; España Fil: Verdura, Sara. Institut Català d'Oncologia; España. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España Fil: Espinoza, Ingrid. University of Mississippi; Estados Unidos Fil: Menendez, Javier A.. Institut Català d'Oncologia; España. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España Fil: Lupu, Ruth. Mayo Clinic; Estados Unidos. University of Ottawa; Canadá. Mayo Clinic Cancer Center; Estados Unidos