EZH2 Mutation and Its Role in Visceral Metastasis in Breast Cancer
Breast cancer remains the most common malignant tumor in women worldwide. While advancements in treatment have improved survival rates, metastatic breast cancer continues to pose a significant challenge, particularly when the cancer spreads to visceral organs such as the liver, lungs, and brain. Patients with visceral metastasis have a significantly worse prognosis compared to those without such metastases. Understanding the mechanisms that drive visceral metastasis is crucial for identifying new therapeutic targets and improving patient outcomes.
Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator involved in gene silencing and cellular differentiation. While EZH2 overexpression has been linked to breast cancer progression, the role of EZH2 mutations in driving visceral metastasis has remained unclear. This study investigates the association between EZH2 mutations and the development of visceral metastasis in breast cancer, with a focus on its role in tumor proliferation, invasion, and resistance to apoptosis.
How the Study Was Conducted
The study analyzed data from 49 patients with metastatic breast cancer, who were pathologically diagnosed at a single medical center. Metastatic tissue samples were collected using ultrasound-guided needle biopsy, and paired peripheral blood samples were also obtained. The samples were subjected to targeted next-generation sequencing using a 247-gene panel to identify genetic alterations, including EZH2 mutations.
In addition to genetic analysis, laboratory experiments were conducted using MDA-MB-231 breast cancer cells engineered to express either wild-type EZH2 or a mutated form (EZH2K515R). These cells were assessed for their ability to proliferate, migrate, invade, and resist apoptosis using cell viability assays, colony formation tests, and flow cytometry.
Key Findings on EZH2 Mutations and Visceral Metastasis
Patients with EZH2 mutations had a significantly higher risk of developing visceral metastasis compared to those without mutations. In the entire cohort, 42.3% of patients with visceral metastasis had EZH2 mutations, whereas only 13.0% of patients without visceral metastasis carried these mutations. Among patients with triple-negative breast cancer, the presence of EZH2 mutations was even more pronounced, with 50% of those with visceral metastasis carrying the mutation, compared to only 10% in those without visceral metastasis.
Multivariate analysis confirmed that EZH2 mutation was an independent prognostic factor for visceral metastasis. Patients with EZH2 mutations had a significantly shorter time to metastasis compared to those without mutations, suggesting that EZH2 alterations accelerate the spread of cancer to distant organs.
The Effect of EZH2 Mutations on Tumor Behavior
Laboratory experiments further demonstrated that the EZH2K515R mutation enhances tumor aggressiveness. Compared to wild-type EZH2, cancer cells with the EZH2 mutation displayed higher rates of proliferation, increased migration and invasion, and reduced apoptosis. The mutation was also associated with an increase in the proportion of cells in the S and G2/M phases of the cell cycle, which is indicative of faster tumor growth.
The study also explored how EZH2 mutations interact with other known breast cancer mutations, such as BRCA1 and BRCA2 alterations. No significant correlation was found between EZH2 and BRCA mutations, suggesting that EZH2-driven metastasis may operate through a distinct molecular pathway.
The findings highlight EZH2 mutation as a key driver of visceral metastasis in breast cancer, particularly in triple-negative breast cancer. These results suggest that testing for EZH2 mutations in metastatic breast cancer patients could help identify those at higher risk of visceral metastasis, allowing for more aggressive monitoring and early intervention.
Given the role of EZH2 in promoting metastasis, targeting EZH2 with specific inhibitors could be a potential treatment for patients with these mutations. Several EZH2 inhibitors are currently in clinical trials for other cancers, and their potential use in metastatic breast cancer warrants further investigation. Additionally, combination therapies that suppress EZH2 activity while enhancing apoptosis could help improve treatment outcomes.
To learn more, read this!: EZH2 mutation is associated with the development of visceral metastasis by enhancing proliferation and invasion and inhibiting apoptosis in breast cancer cells | BMC Cancer | Full Text
