PTEN and its Role in Cowden Syndrome and Sporadic Cancers John Cuningham Biology 445

Phosphatidylinositols are membrane lipids that can be phosphorylated in multiple positions and function as messengers in signaling pathways

The Phosphatidylinositols PIP2 and PIP3 bind to and activate protein kinases Konander D. et al. EMBOJ, 2004

PTEN can function as both a protein and lipid phosphatase

PTEN’s lipid phosphatase activity opposes Phosphoinositude-3-Kinase (PI3K) activity, thus inactivating Akt and other downstream targets

PTEN also exhibits tumor suppressive functions in the nucleus

PTEN is one of the most commonly mutated tumor suppressor genes with a wide variety of cancer-specific mutations

Homozygous loss of PTEN is embryonic lethal with defects in cephalic and caudal patterning and failure of chorio-allantoic development

Functional inactivation of one PTEN allele increases tumor susceptibility in various tissues

PTEN loss in cancer exemplifies complexity with haploinsufficiency and genetic interactions playing a crucial role in tumor susceptibility

Cowden Syndrome This is the most common PTEN harmatoma tumor syndrome (PHTS) 85% of patients with this syndrome have germline PTEN mutations Classically associated with formation of breast cancer, endometrial cancer and thyroid cancer

PTEN also plays a role in many sporadic tumors and is one of the most commonly mutated tumor suppressors

Treatment Options As a tumor suppressor the loss of PTEN function can not currently be replaced by targeted drug therapy, but knowledge of the pathway affected by PTEN loss allows targeting of drugs  PI3k-mTOR-Akt1 pathway Rapamycin-mTor 1/rapamycin/rapamycin.html Perifosine-Akt

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