Metastasis remains the major cause of breast cancer morbidity and mortality, however, its underlying mechanisms are not fully understood and therapeutic strategies to prevent metastatic spread are limited. Researchers from France and the United States sought to determine the mechanisms at play in the development of primary tumors in aggressive breast cancers into metastases. The researchers discovered that a protein found abundantly in breast cancers that are resistant to conventional therapies may be the culprit. Their findings may lead to the development of early treatment to prevent the development of metastases in breast cancer.

The findings are published in Cell Discovery in an article titled, “Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.”

“Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread,” the researchers wrote. “A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize.”

The researchers used high-resolution single-cell RNA-seq from a cohort of breast cancer patients.

“To identify key lysine methyltransferases regulating breast cancer metastasis, we utilized a scRNA-seq dataset of a large cohort of breast cancer patient samples representing all major clinical subtypes,” noted the researchers. “Restricting our analysis to neoplastic cells-only, classified in low or high metastasis potential populations based on metastasis genes signature, we identified SMYD2 and EZH2 as the top two lysine methyltransferases significantly enriched in pro-metastatic cells.”

The team of scientists subsequently attempted to inhibit SMYD2 in mice with primary-stage breast cancer. A comparative analysis of the development of a cancer in treated and untreated mice revealed a correlation between SMYD2 inhibition, the blocking of its action on BCAR3 and the absence of metastasis.

“Our study provides the rationale for therapeutic targeting of SMYD2 activity to prevent breast cancer cells invasiveness and to impede metastasis,” concluded the researchers. “Specifically, we showed that the SMYD2-BCAR3-FMNL signaling pathway could be effectively disrupted by inhibiting SMYD2 enzymatic activity both in vitro and in vivo. Additionally, our data indicated that SMYD2 inhibitors are well tolerated in preclinical animal models and are promising therapeutics to prevent breast cancer metastatic spread, a major unmet clinical need for breast cancer patients.”

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