DNA Methylation-Regulated HOXC8's Role in HER2-Positive Breast Cancer Function and its Contribution to Herceptin Resistance.

Background: The epidermal growth factor receptor 2 () is overexpressed in 30% of breast cancers, and this overexpression is strongly correlated with a poor prognosis. Herceptin is a common treatment for HER2-positive breast cancer; however, cancer cells tend to adapt gradually to the drug, rendering it ineffective. The study revealed an association between the methylation status of the Homeobox C8 () gene and tumor development. Therefore, it is of paramount importance to delve into the interaction between and HER2-positive breast cancer, along with its molecular mechanisms. This exploration holds significant implications for a deeper understanding of the pathophysiological processes underlying HER2-positive breast cancer.

Method: Tumor tissue and pathological data from patients with HER2-positive breast cancer were systematically collected. Additionally, the human HER2-positive breast cancer cell line, SKBR3, was cultured to assess both the expression level of and the degree of DNA methylation. The study aimed to explore the relationship between the relative expression of and the clinical characteristics of breast cancer patients. The expression level of and the promoter methylation of were verified by methylation treatment of SKBR3 breast cancer cells. The regulation of was meticulously carried out, leading to the division of the cells into distinct groups. The study further analyzed the expression levels and biological capabilities within each group. Finally, the and sensitivity of the cells to Herceptin, a common treatment for HER2-positive breast cancer, was measured to assess the efficacy of the drug.

Result: In HER2-positive breast cancer cases characterized by poor methylation, there was an up-regulation of . Its expression was found to be correlated with key clinical factors such as tumor size, lymph node status, clinical tumor, node, metastasis (cTNM) staging, and Herceptin resistance ( < 0.05). Upon methylation of breast cancer cells, there was a significant decrease in expression ( < 0.05). The study revealed that overexpression of resulted in increased proliferation, cloning, and metastasis of HER2-positive breast cancer cells, along with a reduced apoptosis rate ( < 0.05). Conversely, interference with expression reversed this scenario ( < 0.05). A Herceptin-resistant substrain, POOL2, was established using SKBR3 cells. Animal studies demonstrated that overexpressing accelerated tumor development and enhanced POOL2 cells' resistance to Herceptin ( < 0.05). However, following interference with , POOL2 cells exhibited increased responsiveness to Herceptin, leading to a gradual reduction in tumor size ( < 0.05).

Conclusions: In HER2-positive breast cancer, the expression of is elevated in a manner dependent on DNA methylation, and this elevated expression is closely linked to the pathology of the patient. Interfering with expression demonstrates the potential to partially inhibit the development and spread of breast cancer, as well as to alleviate resistance to Herceptin.