The TFE3 protein is a key area of study in biology due to its involvement in certain cancers. TFE3 is a protein produced from instructions provided by the TFE3 gene. It belongs to the basic helix-loop-helix transcription factor family. As a transcription factor, its primary function involves controlling the activity of other genes within a cell.
The Normal Role of the TFE3 Protein
In healthy cells, the TFE3 protein acts as a regulator in various cellular processes. It functions by binding to specific DNA sequences within the regulatory regions of genes to activate their expression.
One of its roles is promoting the creation of lysosomes, often called the cell’s recycling centers. TFE3 also plays a part in initiating autophagy, a process where cells clear out damaged components or unneeded proteins. These functions help cells adapt and survive during periods of stress, such as when nutrients are scarce.
The activity of TFE3 is regulated by the cell’s nutrient status through a protein complex called mTOR. When nutrients are abundant, mTOR keeps TFE3 inactive in the cytoplasm. In conditions of starvation or cellular stress, mTOR activity is inhibited, allowing TFE3 to move into the cell’s nucleus and activate its target genes, promoting cellular adaptation.
TFE3 Gene Fusions in Cancer
A deviation from the normal function of TFE3 occurs when its gene undergoes translocation or fusion. This happens when a piece of one chromosome breaks off and incorrectly attaches to another, resulting in a hybrid, abnormal gene. When the TFE3 gene fuses with another gene, it leads to the production of a new, chimeric protein, not found in healthy cells.
This abnormal TFE3 fusion protein becomes constitutively active, leading to uncontrolled gene expression. This dysregulated activity causes increased movement of the protein into the cell’s nucleus, enhanced binding to DNA, activation of signaling pathways like the PI3K pathway, and ultimately, unchecked cell proliferation. These alterations directly drive cancer development.
Among the cancers linked to TFE3 gene fusions, TFE3-rearranged Renal Cell Carcinoma (RCC) is a common example. This kidney cancer is more frequently observed in children and young adults, accounting for approximately 20% to 40% of pediatric RCC cases, and 1% to 5% of adult RCCs. Various partner genes can fuse with TFE3 in RCC.
Alveolar Soft Part Sarcoma (ASPS) is another cancer driven by TFE3 fusions. In ASPS, the ASPSCR1 gene fuses with TFE3, creating the ASPSCR1::TFE3 fusion protein. This fusion protein acts as an aberrant transcription factor that promotes uncontrolled cell division and the formation of new blood vessels, a process known as angiogenesis, which fuels tumor growth.
Diagnosing TFE3-Associated Tumors
Identifying tumors with TFE3 gene fusions requires specialized laboratory techniques performed by pathologists. One common method is immunohistochemistry (IHC), which uses specific antibodies to detect the TFE3 protein in a tumor tissue sample. A strong and widespread nuclear staining for the C-terminal portion of TFE3 is considered highly indicative of a TFE3-rearranged tumor, with some experts suggesting staining in over 75% of tumor cells as diagnostic.
However, IHC results can be inconsistent due to variations in tissue fixation. For a more definitive diagnosis, fluorescence in situ hybridization (FISH) is widely used. FISH employs fluorescent probes that bind to specific regions of the TFE3 gene on the chromosomes.
When a TFE3 gene rearrangement is present, the probes show a “break-apart” signal pattern. This allows pathologists to confirm the gene fusion. A positive FISH result for TFE3 rearrangement is defined as the detection of characteristic break-apart signals in 15% or more of the analyzed tumor cell nuclei. FISH is often considered the most reliable method for confirming these genetic alterations.
Therapeutic Approaches for TFE3 Cancers
Treatment for TFE3-associated cancers often begins with surgical removal of the tumor for localized disease. For advanced or metastatic cases, systemic therapies are necessary to manage widespread disease. The unique biology of TFE3 fusion proteins guides treatment selection.
Since TFE3 fusion proteins activate pathways that promote angiogenesis, targeted therapies are often used. Tyrosine kinase inhibitors (TKIs) block these pathways, disrupting the tumor’s blood supply and inhibiting its growth. Examples include sunitinib, sorafenib, cabozantinib, and axitinib.
The PI3K/AKT/mTOR signaling pathway is also overactive in TFE3-rearranged renal cell carcinoma. Inhibiting this pathway with drugs like dual PI3K/mTOR inhibitors is another therapeutic option. Immunotherapy is also a significant treatment option.
Immunotherapy drugs activate the body’s immune system to recognize and destroy cancer cells. Combinations of immune checkpoint inhibitors (ICIs) with TKIs have shown encouraging outcomes, particularly in patients with ASPSCR1-TFE3 fusion rearranged RCC. Therapy choice is personalized, depending on the cancer type, stage, and specific TFE3 fusion partner.