differential impact of egfr-targeted therapies on hypoxia responses implications for treatment sensitivity in triple-negative metastatic breast cancer微分egfr-targeted疗法对缺氧反应的影响对三阴性转移性乳腺癌的治疗敏感性的影响.pdfVIP

Differential Impact of EGFR-Targeted Therapies on Hypoxia Responses: Implications for Treatment Sensitivity in Triple-Negative Metastatic Breast Cancer 1,2 2 2 2 3 Abderrahim El Guerrab , Rabah Zegrour , Carine-Christiane Nemlin , Flavie Vigier , Anne Cayre , 3 2 1 Frederique Penault-Llorca , Fabrice Rossignol , Yves-Jean Bignon * ´ 1 Department of Oncogenetic, Centre Jean Perrin, Clermont-Ferrand, France, 2 ADELBIO, Faculty of Medicine, Centre Biomedical de Recherche et Valorisation, Clermont- Ferrand, France, 3 Department of Pathology, Centre Jean Perrin, Clermont-Ferrand, France Abstract Background: In solid tumors, such as breast cancer, cells are exposed to hypoxia. Cancer cells adapt their metabolism by activating hypoxia-inducible factors (HIFs) that promote the transcription of genes involved in processes such as cell survival, drug resistance and metastasis. HIF-1 is also induced in an oxygen-independent manner through the activation of epidermal growth factor receptor tyrosine kinase (EGFR-TK). Triple-negative breast cancer (TNBC) is a subtype of invasive breast cancer characterized by negative expression of hormonal and HER2 receptors, and this subtype generally overexpresses EGFR. Sensitivity to three EGFR inhibitors (cetuximab, gefitinib and lapatinib, an HER2/EGFR-TK inhibitor) was evaluated in a metastatic TNBC cell model (MDA-MB-231), and the impact of these drugs on the activity and stability of HIF was assessed. Methodology/Principal Findings: MDA-MB-231 cell