This model of epithelial cancer combines overexpression of epidermal growth factor receptor (EGFR) with reduced expression of Dmel\psq, a gene involved in transcriptional regulation; no human ortholog of Dmel\psq has been identified. Interactions between tumorigenic epithelial cells and normal mesenchymal cells have been investigated using this disease model system.
Human epidermal growth factor receptor (EGFR) has been implicated in multiple cancers of epithelial derivation. EGFR is a transmembrane receptor kinase that spans the cell membrane and is activated by a number of external ligands, including EGF and transforming growth factor α. Activation of EGFR initiates several signal transduction cascades, leading to DNA synthesis and cell proliferation. There is one orthologous gene in flies, Dmel\Egfr, for which classical amorphic and hypomorphic alleles, constitutively active alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Egfr is orthologous to three additional human genes, ERBB4, ERBB3 and ERBB2. ERBB2 has also been implicated in multiple cancers.
Amorphic mutations of Dmel\Egfr act as recessive embryonic lethals; they also act as cell lethals in somatic clones. Hypermorphic (gain-of-function) alleles result in dominant visible phenotypes. Egfr overexpression in imaginal disc epithelial cells leads to mild overproliferation phenotypes. Reducing expression of the Drosophila gene psq in combination with Dmel\Egfr overexpression results in more severe phenotypes: larvae fail to enter pupariation and the discs continue to grow, often filling the anterior half of the larva; metastatic phenotypes are observed. Dmel\psq was selected as a candidate for investigation based on the fact that the levels of expression of microRNAs mir-10 and mir-375 impact the EGFR phenotypes; the psq transcript is predicted to be a target of these two miRNAs.
See also the human disease model report 'cancer, epithelial, EGFR-microRNA-related' (FBhh0000398).
The human gene Hsap\EGFR has been introduced into flies, using a mutant form that displays constitutive kinase activity and can be expressed in specific tissues using the GAL4-UAS system. Constructs of Hsap\EGFR have been used for human disease models of malignant glioma (FBhh0000399, FBhh0000401, FBhh0000403).
[updated Dec. 2018 by FlyBase; FBrf0222196]