Cowden’s Disease and PTEN

Cowden’s Disease (CD)  A rare autosomal dominant disease similar to Lehrmitte-Duclos Disease (LDD) and Bannayan-Zonana Syndrome (BZS)  Common features: (i) benign tumors (usually hamartomas) in various tissues, (ii) increased hand and foot size, (iii) a predisposition to cancer

Cowden’s Disease – continued…

More than 80% of patients with CD, LDD, or BZS show germline mutations in PTEN Based on these symptoms, PTEN is probably involved in regulating… Growth!

PTEN – The Basics Phosphatase and tensin homolog on chromosome ten

PTEN Crystal Structure

PTEN Biochemistry A protein and lipid tyrosine phosphatase in vitro In the cell its primary substrate is the lipid phosphatidylinositol (3, 4, 5) triposphate (a.k.a. PIP3). It acts as an antagonist of PI3kinase (a.k.a. PI3K), which phosphorylates PIP2.

PTEN Pathway – The Short Version

PTEN Pathway – Introducing AKT

PTEN and Cancer Inactivation of one allele creates an environment conducive to tumor growth. Tumor Suppressor Next comes LOH, which is seen in 25 – 50% of all primary tumors. Mutations of both alleles are found in most types of cancer. Only p53 is mutated more frequently

PTEN and Cancer – continued… PTEN loss of function mutations occur often in glioblastoma, late stage prostate cancer, and endometrial cancer. For other cancers complete loss of PTEN function usually occurs in late stage tumors.

PTEN and Cancer – continued…

Model Organisms PTEN -/- is embryonic lethal in mice PTEN +/- mice, including ES chimeras, displayed intestinal polyps and increased skin thickness, similar to symptoms of CD, LDD, and ZBS. Malignant tumors were also found in several PTEN +/- mice at a young age

Model Organisms – continued…

PTEN – Additional Effects So far we’ve focused on growth, but there’s more… “PTEN has been shown to influence growth, survival, cell cycle progression, cell motility and migration and angiogenesis…”

PTEN – Additional Effects