PTEN Tumor Suppressor and Cancer Taryn Miner BIOL445

PTEN is a Lipid Phosphatase Heinrich et. al. PTEN, or phosphatase and tensin homolog, is a lipid phosphatase that is present in nearly all bodily tissues. The PTEN gene is located on the long (q) arm of chromosome 10. Fully functional PTEN requires two domains: the phosphatase domain and the C2, or lipid membrane-binding domain. PTEN is essential for development, as PTEN double mutant mice are embryonic lethal. It was recently found that PTEN acts as a homodimer.

PTEN is a Tumor Suppressor PTEN is a lipid phosphatase that acts as a negative regulator of the PI3K–AKT–mTOR pathway, which is an important regulator of cell growth and survival. PTEN’s normal job in the cell as a tumor suppressor is to inhibit this pathway by dephosphorylating the second messenger phosphatidylinositol-3, 4, 5-triphosphate. This second messenger activates Akt and PDK1, which are survival kinases that promote cell survival and proliferation and inhibit apoptosis. PTEN also works to protect the genome

PTEN loss causes cancer in mice When PTEN function is lost, the cell is unable to prevent cell division. Heterozygous mice develop tumors in the breast, skin, intestine, thyroid, and brain. Overexpression of PTEN in mice has shown to promote apoptosis and inhibit cell cycle progression, colony formation, and cellular migration. After p53, PTEN is the second most mutated tumor suppressor in cancers. Cancer caused by loss of PTEN function can be sporadic or hereditary.

PTEN upregulation affects the cell cycle and apoptosis Cell lines were transfected with no plasmid (control), a control plasmid (pc-DNA3.1), or a plasmid with the PTEN gene. Upregulation of the PTEN protein causes significantly higher percentages of apoptotic cells than controls. Upregulation of PTEN also causes halt in cell cycle progression as more cells are in G1 phase than controls and less cells are in S phase than controls. Sun et. al.

PTEN loss promotes angiogenesis in Zebrafish Zebrafish have two PTEN proteins, PTENA and PTENB. Homozygous double knockout zebrafish exhibit angiogenesis to tumors. Choorapoikayil et. al.

Loss of PTEN function is common in many human cancers and is often caused by LOH Most cases of cancer caused by loss of PTEN function are due to LOH rather than biallelic inactivation by mutation or homozygous deletion. Some recent research has shown that happloinsufficiency of PTEN promotes cancer progression. Perren et. al.

PTEN mutations can be hereditary Cowden Syndrome is the most common of the PTEN hamartoma tumor syndromes, which are all characterized by benign skin tumors (hamartomas) and a significantly increased risk for developing cancers of the breast, endometrium, thyroid, CNS, prostate, pancreas, liver, and many more. 85% of Cowden Syndrome patients have germline mutations, meaning they inherited one non-functional copy of PTEN. Cowden Syndrome is inherited in an autosomal dominant pattern, similar to retinoblastoma, and so only requires “one hit” to cause cancer in CS patients.

Treatment for cancers caused by PTEN loss Treatment for cancers caused by the loss of PTEN function include PI3K inhibitors, mTOR inhibitors, Akt inhibitors, or dual inhibitors. Lee et. al.

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