Cowden Syndrome PTEN Mouse Models PTEN & Cowden syndrome

CS was first reported in 1963 An autosomal dominant disorder 1 in 200,000 to 1 in 250,000 An inherited multi-system disease

manifested by macrocephaly, multiple hamartomas, papillomas, mucocutaneous lesions and a predisposition for developing carcinoma of the breast, thyroid and endometrium.

Butler et. Al., 2005

Bussaglia, 2002

Bussaglia et. Al, 2002; Schreibman et. Al., 2005.

PTEN= Phosphatase and tensin homolog

Location of PTEN gene: chromosome 10q23 (a chromosomal region subjects to frequent LOH).

PTEN gene is composed of 9 exons and encodes a polypeptide of 403 amino acids.

As a protein phosphatase: dephosphorylate protein substrates.

As a lipid phosphatase: removes the phosphate from phosphatidylinositol 3,4,5-triphosphate (PIP3) regulates the action of the phosphatidylinositol 3-kinase (PI3K).

As a tumor suppressor: PTEN is a critical negative regulator of the PI3K pathway through its lipid phosphatase activity.

Different locations, different ways of maintaining genomic stability A hallmark of cancers!

PTEN at nucleus: novel functions discovered Nuclear PTEN in maintenance of chromosomal stability has been demonstrated in both mouse and human systems: 1. PTEN interacts with centromeres 2. PTEN may be necessary for DNA repair

Mice with a complete null mutation of PTEN Early embryonic lethality PTEN is essential for normal embryogenesis

Half of PTEN+/– mice die within 1 year of birth.

PTEN+/- survivors develop a broad range of tumors, including mammary, thyroid, endometrial and prostate cancers, as well as T-cell lymphomas. PTEN is a powerful and distinct tumor suppressor.

In mice, PTEN deficiency causes increases in cell proliferation, apoptotic resistance, centromeric instability, and DNA double-strand breaks.

All of these defects enhance an animal's susceptibility to carcinogens and the occurrence of secondary genetic or epigenetic alterations that can lead to cancer development.

Germline mutation of one allele of PTEN results in hereditary cancer predisposition.

Mutations are scattered along the entire gene.

Loss of function of the PTEN gene are found in approximately 80% of patients with CS:1. Missense mutation: mostly occurs in exon 5 of PTEN encoding the core motif of the phosphate domain.2. Loss of heterozygosity (LOH): loss of wield-type allele.

Cowden syndrome patients are at increased risk to develop breast, thyroid, and endometrial cancer.

The lifetime risk of: - breast cancer in women with CS is estimated to be as high as 50%, as compared to 11% within the general population.- thyroid cancer in both genders is estimated to approach10%, as compared to less than 1% in the general population.- Endometrial cancer is more frequent in women with CS with an estimated risk of 5–10% as compared to <2.5% in the general population

Other malignancies have anecdotally been reported to be increased with CS.