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

## TL;DR

Removing a specific protein in mice leads to increased skin tumor growth, but blocking related proteins can significantly reduce tumors.

## Contribution

This study identifies compensatory ErbB signaling as a novel driver of skin tumorigenesis in mice lacking Tpl2, suggesting new therapeutic strategies.

## Key findings

- Tpl2−/− mice develop 12-fold more papillomas and 4-fold more cSCCs compared to wild-type mice.
- Inhibiting EGFR or HER2 with Gefitinib or Lapatinib reduces tumor burden in Tpl2−/− mice.
- Tpl2 loss increases EGFR, HER2, and HER3 gene expression and activates ErbB signaling in papillomas.

## Abstract

The mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in cellular growth and survival, and its disruption is associated with various cancers. Loss or alteration of critical regulatory proteins in this pathway can trigger compensatory mechanisms that activate alternative signaling routes that promote tumor development. This study demonstrates that loss of a specific MAPK family member, Tpl2, leads to upregulation of growth factor receptors and associated signaling molecules, resulting in dramatically increased tumor formation in mice. Importantly, targeted inhibition of these upregulated receptors significantly reduced tumor burden, suggesting that therapeutic strategies focused on blocking compensatory signaling pathways could be valuable for treating cancers that arise from MAPK pathway dysfunction.

Background: The mitogen-activated protein kinase (MAPK) signaling pathway is frequently dysregulated in cutaneous squamous cell carcinoma (cSCC). Tumor progression locus 2 (Tpl2), a serine/threonine protein kinase within the MAPK family, regulates cellular proliferation, survival, and inflammatory responses. Loss of Tpl2 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 Tpl2−/− mice. Methods: To evaluate whether aberrant ErbB signaling drives tumorigenesis in Tpl2−/− mice, wild-type (Tpl2+/+) 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. Results: We found that Tpl2 ablation increases gene expression of EGFR, HER2, and HER3, while baseline protein levels remain unchanged between Tpl2 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 Tpl2−/− keratinocytes. Further, Tpl2 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. Tpl2−/− mice developed 12-fold more papillomas and 4-fold more cSCCs compared to Tpl2+/+ animals. Treatment with Gefitinib or Lapatinib reduced papilloma numbers by 88% and 50%, respectively, while restoring cSCC numbers to Tpl2+/+ levels. Conclusions: These findings indicate that ErbB targeting represents a promising therapeutic strategy for cSCCs arising from MAPK pathway dysregulation.