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EGFR is a Therapeutic Target in Hormone Receptor-Positive Breast Cancer
- Source :
- Cellular Physiology and Biochemistry, Vol 53, Iss 5, Pp 805-819 (2019)
- Publication Year :
- 2019
-
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.
- Subjects :
- 0301 basic medicine
Adult
TGF alpha
Physiology
Receptor, ErbB-2
Estrogen receptor
Mice, Nude
Antineoplastic Agents
Breast Neoplasms
lcsh:Physiology
lcsh:Biochemistry
03 medical and health sciences
Mice
0302 clinical medicine
Gefitinib
Breast cancer
Downregulation and upregulation
Cell Line, Tumor
Medicine
Animals
Humans
lcsh:QD415-436
Epidermal growth factor receptor
skin and connective tissue diseases
Aged
Neoplasm Staging
Proportional Hazards Models
lcsh:QP1-981
biology
business.industry
Estrogen Receptor alpha
Middle Aged
medicine.disease
Survival Rate
Tamoxifen
030104 developmental biology
Receptors, Estrogen
Hormone receptor
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer research
biology.protein
Female
Neoplasm Grading
business
medicine.drug
Subjects
Details
- ISSN :
- 14219778
- Volume :
- 53
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
- Accession number :
- edsair.doi.dedup.....45313c47942549485d67150e47a1096f