Increased EGFR/HER2 Pathway Activation Contributes to Skin Tumorigenesis in Tpl2−/− Mice

<b>Background:</b> The mitogen-activated protein kinase (MAPK) signaling pathway is frequently dysregulated in cutaneous squamous cell carcinoma (cSCC). Tumor progression locus 2 (<i>Tpl2</i>), a serine/threonine protein kinase within the MAPK family, regulates cellular proliferation, survival, and inflammatory responses. Loss of <i>Tpl2</i> activates compensatory signaling cascades, driving increased papilloma and cSCC development. In this study we examined whether dysregulated ErbB signaling contributes to the enhanced tumor burden found in <i>Tpl2</i>^-/- mice. <b>Methods</b>: To evaluate whether aberrant ErbB signaling drives tumorigenesis in <i>Tpl2</i>^-/- mice, wild-type (<i>Tpl2</i>^+/+) and Tpl2^-/- mice were subjected to a two-stage chemical carcinogenesis protocol for 48 weeks. A subset of mice received Gefitinib (an EGFR inhibitor) or Lapatinib (a HER2 inhibitor) in their diet. <b>Results</b>: We found that <i>Tpl2</i> ablation increases gene expression of EGFR, HER2, and HER3, while baseline protein levels remain unchanged between <i>Tpl2</i> genotypes. To investigate the possibility of microRNA (miR)-mediated post-transcriptional regulation of EGFR, HER2, and HER3, we measured ErbB-related miR expression in keratinocytes. We found that HER2/3-related miRs 205 and 21 are increased in <i>Tpl2</i>^-/- keratinocytes. Further, <i>Tpl2</i> loss enhances p-EGFR, EGFR, and HER2 protein expression in papillomas. and HER2-related microRNAs (miRs) 205 and 21 in keratinocytes, and enhances p-EGFR, EGFR, and HER2 protein expression in papillomas. <i>Tpl2</i>^-/- mice developed 12-fold more papillomas and 4-fold more cSCCs compared to <i>Tpl2</i>^+/+ animals. Treatment with Gefitinib or Lapatinib reduced papilloma numbers by 88% and 50%, respectively, while restoring cSCC numbers to <i>Tpl2</i>^+/+ levels. <b>Conclusions</b>: These findings indicate that ErbB targeting represents a promising therapeutic strategy for cSCCs arising from MAPK pathway dysregulation.