Tumor suppressor genes act within the genome to regulate cell growth and proliferation. They also help with DNA repair mechanisms and other important cellular signalings such as the apoptosis pathway. Without functional tumor suppressor genes, there is a high risk of dysregulated cell growth that can lead to malignancy. Loss of function mutations in tumor suppressor genes has been identified in many types of cancers, including ovarian, lung, colorectal, head and neck, pancreatic, uterine, breast, and bladder cancer. There are even familial cancer syndromes associated with the loss of certain tumor suppressor genes like Li-Fraumeni syndrome and the loss of TP53. The scientific community is studying many tumor suppressor genes, and hopefully, a better understanding of the pathophysiology that leads to oncogenesis will inform the rational design of novel therapies.
Most of our current understanding of tumor suppressor genes comes from the initial studies of the retinoblastoma (RB) gene. This was the first tumor suppressor gene discovered and mutations in RB cause childhood retinoblastoma. This is an inherited condition caused by an inactivating mutation in the RB1 gene that causes a 10,000-fold increased risk of developing retinoblastoma (often in both eyes) as compared to the general population. These patients are also at increased risk of developing osteosarcoma and other sarcomas. Interestingly, about 60% of retinoblastomas occur sporadically (almost always in one eye), and these patients are not at increased risk for other forms of cancer. To explain this dichotomy, Knudson proposed a “two-hit” hypothesis:
Based on these original observations, there are three important properties of classic tumor suppressor genes (TSGs):
Tumor suppressor genes function to either repress or inhibit the cell cycle or promote apoptosis. The more specific functions of tumor suppressor proteins fall into several categories including:
There are many tumor suppressor genes that have been studied, and there are likely many more that have yet to be discovered. The mechanisms of each tumor suppressor gene and its protein products are complex and interrelated to other cell signaling pathways, but some better-known mechanisms are described below.
The retinoblastoma gene encodes the RB protein which normally functions to prevent the cell from entering S phase of the cell cycle. It binds to E2F, inhibiting its function as a transcription factor. This interaction blocks the transcription of genes necessary for DNA replication, and so the cells remain in the G1 phase of the cell cycle.
TP53 Tumor Suppressor Gene
The TP53 tumor suppressor gene is also known as the “guardian of the genome” as it serves to identify DNA damage, pause cell cycle progression to allow for repair, and when repair is not possible, to induce apoptosis. Loss of p53 can cause continued cell replication despite DNA damage and failure to activate programmed cell death. The TP53 gene encodes for the p53 protein which, like RB, prevents the cell from entering S phase. It does this by inhibition of cyclin-dependent kinase 4 (Cdk-4) via transcription of the p21 protein. Besides regulating the cell cycle, p53 can induce apoptosis where cell damage is severe. It does this by activating the BAX gene which encodes a pro-apoptotic protein. P53 also works to inhibit the BCL2 anti-apoptotic gene and stimulates the release of cytochrome c from the mitochondria. Cytochrome c activates caspases within the cell responsible for its eventual degradation.
Phosphatase and Tensin Homolog (PTEN) Gene
The phosphatase and tensin homolog (PTEN) gene negatively regulates the phosphoinositide-3-kinase (PI3K)-AKT and the target of mTOR signaling pathways, which are vital for cell proliferation, cell cycle progression, and apoptosis. The PTEN protein also functions to keep migration, adhesion, and angiogenesis in check. It also plays a role in the overall stabilization of the genome.
Normal cells stop proliferating once they come into contact with neighboring cells. This helps to maintain the structure and architecture of the tissue and is referred to as contact inhibition. Mediation of cell-to-cell contact in many tissues is the function of a group of proteins called cadherins. E-cadherin (epithelial cadherin) regulates contact inhibition by binding to a key component of the WNT signaling pathway, ß-catenin. This binding prevents E-catenin from translocating to the nucleus of the cell, stopping it from activating transcription of pro-growth target genes. Overall, this interaction regulates the morphology and organization of epithelial cell linings. Another tumor suppressor gene, NF2, encodes Neurofibromin-2, better known as Merlin, which acts downstream of E-cadherin to assist with contact inhibition.
BRCA 1, BRCA 2, PARP-1
BRCA1 and BRCA2 are tumor suppressor genes that encode proteins involved in the repair of DNA double-strand breaks through the homologous recombination repair pathway. PARP-1 encodes a protein that assists with the repair of single-stranded breaks in the DNA. Without functional proteins that repair DNA, the cell cycle continues to pass along defective and mutated genetic material that leads to aberrant daughter cells.
The APC gene encodes a tumor suppressor protein that blocks the Wnt signaling pathway, which functions to enhance axis patterning of cells during embryogenesis, cell migration, and cell proliferation. The APC protein is also involved in apoptosis.