# MSLN-mediated activation of EGFR-ERK1/2 signaling drives liver metastasis in breast cancer

## TL;DR

This study identifies mesothelin (MSLN) as a key driver of liver metastasis in triple-negative breast cancer and shows that targeting MSLN can inhibit this process.

## Contribution

The study reveals a novel mechanism involving MSLN-mediated activation of the EGFR-ERK1/2 pathway in promoting liver metastasis in TNBC.

## Key findings

- MSLN is significantly upregulated in metastatic TNBC cells and tissues.
- MSLN activates the EGFR-ERK1/2 signaling pathway to promote TNBC cell survival and proliferation.
- Targeting MSLN with paclitaxel/carboplatin inhibits liver metastasis in a mouse model.

## Abstract

Breast cancer (BC) is the most prevalent malignant disease affecting female patients globally, with triple-negative breast cancer (TNBC) being the subtype linked to the poorest clinical outcome. The liver is a frequent metastatic site of breast cancer. Therefore, elucidating the mechanism underlying liver metastasis in TNBC is crucial for identifying effective diagnostic and therapeutic targets, which holds significant potential for guiding clinical treatment. This study aimed to identify key genes driving breast cancer liver metastasis and to explore their functional mechanisms. Using RNA sequencing of metastatic 4T1-HM3 and primary 4T1-Pri tumor cells, mesothelin (MSLN) was identified as significantly upregulated in metastatic TNBC cells and tissues, as confirmed by qRT-PCR, Western blot, and immunohistochemistry. Further investigations revealed that MSLN overexpression is strongly correlated with liver metastasis compared to metastases at other sites. Mechanistically, MSLN binds to epidermal growth factor receptor (EGFR) and activates the EGFR-ERK1/2 signaling axis, thereby promoting TNBC cell survival and proliferation during metastasis. Importantly, targeting MSLN with a paclitaxel/carboplatin combination effectively inhibited liver metastasis of hepatotropic TNBC in a mouse model. Therefore, our study elucidates the role of the MSLN-mediated EGFR-ERK1/2 signaling pathway in TNBC liver metastasis and highlights potential targeted therapies for treating TNBC liver metastasis.