Academic Frontline｜Professor Zeng Xiaohua's Team Unveils New Mechanism by Which Her2 Promotes Early Breast Cancer Metastasis, Paving the Way for More Precise Diagnostic and Therapeutic Approaches

Recently, Professor Zeng Xiaohua’s team from the Breast Cancer Center at Chongqing University Cancer Hospital published their research in Cell Communication and Signaling (JCR Q1, IF: 8.2), titled "Her2 Promotes Early Dissemination of Breast Cancer by Inhibiting the p38 Pathway Through the Downregulation of MAP3K4." This study offers new insights into the mechanism by which Her2 facilitates early metastasis in breast cancer.

Research Background:

Breast cancer remains a major health threat to women, with metastasis being the leading cause of mortality. While metastasis was traditionally thought to occur only in the later stages of cancer, growing evidence indicates that cancer cells can spread to distant organs as early as the initial stages of the disease, even before the primary tumor is detectable—a phenomenon known as early metastasis. This is particularly prominent in Her2-positive breast cancer, with around 2-3% of ductal carcinoma in situ (DCIS) patients exhibiting metastatic spread before the primary tumor has even formed. However, the underlying mechanisms have not been fully elucidated.

Research Methods:

In vitro, protein expression and phosphorylation levels were assessed using Western blotting, and cell migration and invasion abilities were evaluated using Transwell assays. Three-dimensional (3D) cell organoid cultures were utilized to observe cell invasion. In vivo, xenograft mouse models were constructed to observe tumor growth and metastasis, and blood, bone marrow, and lung tissues were collected to quantify early disseminated cancer cells.

Research Findings:

The study discovered that in Her2-positive DCIS cells and tissues, the expression of the upstream kinase MAP3K4 was downregulated. Overexpression of Her2 significantly reduced both the mRNA and protein levels of MAP3K4 in MCF-10A and HMEC cells, inhibiting p38 phosphorylation and promoting epithelial-mesenchymal transition (EMT), which enhanced cell migration and invasion. Restoring MAP3K4 expression reversed these changes. Further investigation revealed that Her2 inhibits MAP3K4 transcription by downregulating the transcription factor HOXB13. In the DCIS database, HOXB13 expression showed a significant positive correlation with MAP3K4. Overexpression of Her2 suppressed HOXB13 expression, while the Her2 inhibitor Lapatinib upregulated both HOXB13 and MAP3K4. Moreover, HOXB13 directly binds to the MAP3K4 promoter to activate its transcription, and mutations in key binding sites disrupted this activation process.

Animal experiments confirmed that in a xenograft mouse model constructed with MCF10DCIS.COM cells, Her2 overexpression promoted early metastasis of cancer cells, whereas overexpression of MAP3K4 or HOXB13 inhibited this process. Knockdown of MAP3K4 restored the cancer cell’s metastatic ability.

Figure 1. Her2 promotes early dissemination of breast cancer via MAP3K4.

Figure 2. Her2 enhances early metastasis of breast cancer through the HOXB13-MAP3K4 pathway.

Figure 3. HOXB13 directly binds to the MAP3K4 promoter region, regulating its transcription.

Figure 4. The Her2-HOXB13-MAP3K4 signaling pathway promotes early dissemination of tumor cells in vivo.

Conclusion:

This study reveals that Her2 promotes early breast cancer metastasis by downregulating HOXB13, inhibiting MAP3K4 transcription, and suppressing the p38 signaling pathway. This discovery provides new insights into the mechanisms of early breast cancer metastasis and suggests that upregulating HOXB13 or MAP3K4, or activating the p38 pathway, may offer effective therapeutic strategies to prevent early metastasis in Her2-positive breast cancer. This research lays the theoretical foundation for the development of more precise diagnostic methods and targeted therapies, offering hope for improving the prognosis of breast cancer patients.

Source: Wang, G., Wen, P., Xue, T. et al. Her2 promotes early dissemination of breast cancer by inhibiting the p38 pathway through the downregulation of MAP3K4. Cell Commun Signal 22, 611 (2024). https://doi.org/10.1186/s12964-024-02000-2