Autocrine-derived epidermal growth factor receptor ligands contribute to recruitment of tumor-associated macrophage and growth of basal breast cancer cells in vivo

Nicole K. Nickerson, Christopher P. Mill, Hsin Jung Wu, David J. Riese, John Foley

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Epidermal growth factor receptor (EGFR) expression has been linked to progression of basal breast cancers. Many breast cancer cells harbor the EGFR and produce its family of ligands, suggesting they may participate in autocrine and paracrine signaling with cells of the tumor microenvironment. EGFR ligand expression was profiled in the basal breast cancer cell line MDA-231 where AREG, TGF-α, and HBEGF were the three ligands most highly expressed. Autocrine signaling was modulated through silencing or overexpression of these three ligands using lentiviral constructs and the impact measured using motility, proliferation, and cytokine expression assays. Changes in receptor phosphorylation and receptor turnover were examined. Knockdown of AREG or TGF-α in vitro resulted in decreased motility (p < 0.05) and decreased expression of macrophage chemoattractants. Overexpression of TGF-α increased motility and chemoattractant expression, whereas AREG did not. HBEGF modulation had no effect on any cellular behaviors. All the cells with altered ligand production were inoculated into female athymic nude mice to form mammary fat pad tumors, followed by immunohistochemical analysis for necrosis, angiogenesis, and macrophage recruitment. In vivo, knockdown of AREG or TGF-α increased survival (p < 0.001) while decreasing angiogenesis (p < 0.001), tumor growth (p < 0.001), and macrophage attraction (p < 0.001). Overexpression of AREG appeared to elicit a greater effect than TGF-α on mammary fat pad tumor growth by increasing angiogenesis (p < 0.001) and macrophage attraction to the tumor (p < 0.01). We propose these changes in mammary tumor growth were the result of increased recruitment of macrophages to the tumor by cells with altered autocrine EGFR signaling. We conclude that AREG and TGF-α were somewhat interchangeable in their effects on EGFR signaling; however, TGF-α had a greater effect in vitro and AREG had a greater effect in vivo.

Original languageEnglish (US)
Pages (from-to)303-317
Number of pages15
JournalOncology Research
Volume20
Issue number7
DOIs
StatePublished - Jun 18 2013

Keywords

  • Amphiregulin
  • Breast cancer
  • Epidermal growth factor receptor ((EGFR)
  • Macrophage colony-stimulating factor-1 (MCSF-1)
  • Transforming growth factor-α (TGF-α)

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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