The Role of a Transcription Factor in Triple-Negative Breast Cancer Progression

Scientists have identified a molecular mechanism that plays a role in the progression and spread of triple-negative breast cancer (TNBC). The findings may help offer therapeutic targets in the future.

Previously, the investigators identified musculoaponeurotic fibrosarcoma (MAF) oncogene family protein K (MAFK) as a gene that is switched on by TGF-β, a protein known to play a role in TNBC development. In a study published in Science Signaling, the investigators confirmed MAFK as a functional link between TGF-β and TNBC.

“The TGF-β signaling pathway is involved in TNBC progression and metastasis,” said corresponding author Mitsuyasu Kato. “However, it’s also involved in beneficial process in healthy cells, and actually helps to suppress the early stages of tumor development. Identifying molecular processes downstream of the TGF-β pathway could offer specific targets for TNBC therapy to combat progression and metastasis without interfering with the beneficial effects of TGF-β signaling.”

In the study, the investigators found that TNBC cells contained higher levels of MAFK than any other breast cancer cell types. After conducting a survey of patient data, the investigators found that patients with higher MAFK gene activity had poorer prognosis.

When the investigators interfered with the production of MAFK in breast cancer cells, they found that the formed tumors were smaller and metastasized to a lesser degree. Conversely, when non-cancerous breast cells were genetically engineered to produce MAFK, it caused them to behave like cancer cells.

Although prior evidence has shown MAFK promotes tumor development in other cancer types, the underlying mechanism remained unknown. In the current study, the investigators screened DNA to identify the gene GPNMB, which is switched on by MAFK.

“We found that induction of MAFK of cancer-like behaviors in breast cells is dependent on GPNMB,” said lead author Yukari Okita. “GPNMB is already known to be present at high levels in the most aggressive and lethal TNBC and to contribute to cancer development; our study identifies induction by MAFK as a missing link between the TGF-β pathway and GPNMB.”