Yisun Jeong 1,2 , Soo Youn Bae 3 , Daeun You 1,2 , Seung Pil Jung 3 , Hee Jun Choi 2,4 , Isaac Kim 2,4 , Se Kyung Lee 2,4 , Jonghan Yu 2,4 , Seok Won Kim 2,4 , Jeong Eon Lee 1,2,4 , Sangmin Kim 5 , Seok Jin Nam 6,4 Show Affiliations »
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. © Copyright by the Author(s). Published by Cell Physiol Biochem Press.
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. © Copyright by the Author(s). Published by Cell Physiol Biochem Press.
Entities: Chemical
Disease
Gene
Species
Keywords:
Estrogen receptor; EGFR; Endocrine therapy; Tamoxifen resistance
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Year: 2019
PMID： 31670920 DOI： 10.33594/000000174
Source DB: PubMed Journal: Cell Physiol Biochem ISSN： 1015-8987