EGFR is a therapeutic target in hormone receptor-positive breast cancer

Yisun Jeong, Soo Youn Bae, Daeun You, Seung Pil Jung, Hee Jun Choi, Isaac Kim, Se Kyung Lee, Jonghan Yu, Seok Won Kim, Jeong Eon Lee, Sangmin Kim, Seok Jin Nam

Research output: Contribution to journalArticle

Abstract

Background/Aims: Despite effective therapeutic strategies for treating hormone receptor-positive (HR+) breast cancer, resistance to endocrine therapy that is either de novo or acquired still occurs. We investigated epidermal growth factor receptor (EGFR) as a therapeutic target for overcoming endocrine resistance in HR+ breast cancer models. Methods: Using clinical data from 2,166 patients who had HR+ breast tumors and received tamoxifen, we analyzed survival rates. Levels of mRNA and protein expression were analyzed by real-time PCR and western blotting, respectively. Cell viability was analyzed by MTT assays and anchorage-independent growth by soft agar colony-formation assays. Efficacy of tamoxifen and/or gefitinib was analyzed using orthotopic xenograft mouse models. Results: EGFR expression was significantly associated with more advanced stage and higher grade. EGFR expression was different in luminal A-like (Lum A, 1.3%) versus luminal B-like (Lum B, 11.4%) subtypes. On multivariate analyses for survival Lum B subtype EGFR+ tumors showed a hazard ratio (HR) of 5.22 (95% CI, 1.29-21.15, P = 0.020) for overall survival (OS) and HR of 2.91 (95% CI, 1.35-6.28, P = 0.006) for disease-free survival (DFS). Levels of EGFR inversely correlated with ER-α expression. Basal ER-α level was completely blocked by TGFA or EGF treatment. With TGFA pretreatment, ER+ breast cancer cells were resistant to 4-hydroxytamoxifen (4-OHT). Conversely, downregulation of ER-α by TGFA was reversed by gefitinib with recovered sensitivity to 4-OHT. Tumorigenicity of EGFR and ER+ breast cancer cells were significantly decreased by combined tamoxifen and gefitinib. Conclusion: Aberrant EGFR expression was associated with poor prognosis in ER+ breast cancers, especially the Lum B subtype. Loss of ER by EGFR activation induced tamoxifen resistance. Therefore, EGFR could be a therapeutic target for overcoming recurrence of ER+ breast cancer with high EGFR expression.

Original languageEnglish
Pages (from-to)805-819
Number of pages15
JournalCellular Physiology and Biochemistry
Volume53
Issue number5
DOIs
Publication statusPublished - 2019 Jan 1

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Keywords

  • EGFR
  • Endocrine therapy
  • Estrogen receptor
  • Tamoxifen resistance

ASJC Scopus subject areas

  • Physiology

Cite this

Jeong, Y., Bae, S. Y., You, D., Jung, S. P., Choi, H. J., Kim, I., Lee, S. K., Yu, J., Kim, S. W., Lee, J. E., Kim, S., & Nam, S. J. (2019). EGFR is a therapeutic target in hormone receptor-positive breast cancer. Cellular Physiology and Biochemistry, 53(5), 805-819. https://doi.org/10.33594/000000174