Abstract
BackgroundIn 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 FindingsMDA-MB-231 cells were genetically modified to stably express an enhanced green fluorescent protein (EGFP) induced by hypoxia; the Ca9-GFP cell model reports HIF activity, whereas GFP-P564 reports HIF stability. The reporter signal was monitored by flow cytometry. HIF-1 DNA-binding activity, cell migration and viability were also evaluated in response to EGFR inhibitors. Cell fluorescence signals strongly increased under hypoxic conditions (> 30-fold). Cetuximab and lapatinib did not affect the signal induced by hypoxia, whereas gefitinib sharply reduced its intensity in both cell models and also diminished HIF-1 alpha levels and HIF-1 DNA-binding activity in MDA-MB-231 cells. This gefitinib feature was associated with its ability to inhibit MDA-MB-231 cell migration and to induce cell mortality in a dose-dependent manner. Cetuximab and lapatinib had no effect on cell migration or cell viability.ConclusionResistance to cetuximab and lapatinib and sensitivity to gefitinib were associated with their ability to modulate HIF activity and stability. In conclusion, downregulation of HIF-1 through EGFR signaling seems to be required for the induction of a positive response to EGFR-targeted therapies in TNBC.
Highlights
Breast carcinomas have been classified into the following clinicopathological subtypes based on molecular profiling: luminal, human epidermal growth factor receptor (HER2) overexpressing, normal-like, and basal-like breast cancers (BLBCs) [1]
Resistance to cetuximab and lapatinib and sensitivity to gefitinib were associated with their ability to modulate hypoxia-inducible factors (HIFs) activity and stability
Downregulation of hypoxia-inducible factor 1 (HIF-1) through epidermal growth factor receptor (EGFR) signaling seems to be required for the induction of a positive response to EGFR-targeted therapies in Triple-negative breast cancer (TNBC)
Summary
Breast carcinomas have been classified into the following clinicopathological subtypes based on molecular profiling: luminal, human epidermal growth factor receptor (HER2) overexpressing, normal-like, and basal-like breast cancers (BLBCs) [1]. BLBCs express basal markers such as cytokeratins and epidermal growth factor receptor (EGFR) and are generally negative for HER2 expression and both the progesterone and estrogen receptors [2,3,4] This breast cancer subtype is called triple-negative breast cancer (TNBC) and represents about 15% of invasive breast carcinomas. As mentioned previously, EGFR expression is seen in a majority of TNBC cases, providing a potential targeted therapy [6]. In solid tumors, such as breast cancer, cells are exposed to hypoxia. 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
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.