Heregulin drives endocrine resistance by altering il-8 expression in er-positive breast cancer

Adriana Papadimitropoulou, Luciano Vellon, Ella Atlas, Travis Vander Steen, Elisabet Cuyàs, Sara Verdura, Ingrid Espinoza, Javier A. Menendez, Ruth Lupu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number7737
Pages (from-to)1-15
Number of pages15
JournalInternational journal of molecular sciences
Volume21
Issue number20
DOIs
StatePublished - Oct 2 2020

Keywords

  • Autocrine
  • Cytokines
  • IL-8
  • Luminal
  • Tamoxifen

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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