title: The gene dosage of class Ia PI3K dictates the development of PTEN hamartoma tumor syndrome.
abstract: The PTEN hamartoma tumor syndrome (PHTS) is a complex disorder caused by germline inactivating mutations of the tumor suppressor gene PTEN. Loss of PTEN function leads to unimpeded phosphatidylinositol-3'-kinase (PI3K) activity and PI3K-driven cell division. Individuals with PHTS develop benign hamartomas in various tissues and have an increased risk of developing malignant diseases. Notably, no effective therapy currently exists for this disorder. Using both genetic mouse models and pharmacological approaches, we recently demonstrated that PI3K p110α and p110β isoforms play spatially distinct but concerted roles in the skin that are required for the development and maintenance of PHTS. We also show that treatment with a pan-PI3K inhibitor prevents the development of skin PHTS and reverses advanced-stage skin hamartomas in vivo. Here, we report that genetic ablation of only 3 out of 4 p110 alleles is sufficient to block the development of skin hamartomas resulting from the complete loss of Pten in mice. Similar to our findings in skin, we now also show that mammary gland neoplastic lesions can be prevented or reversed upon PI3K inhibition in our PHTS mouse model. Our data suggest a possible route to chemoprevention using reduced doses of PI3K inhibitors for PTEN-deficient carrier patients.
authors.affiliation: Department of Cancer Biology; Dana-Farber Cancer Institute; Boston, MA USA; Department of Biological Chemistry and Molecular Pharmacology; Harvard Medical School; Boston, MA USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
mesh_terms: D000483:Alleles; D000631:Aminopyridines / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D006223:Hamartoma Syndrome, Multiple / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009025:Morpholines / Q000737:chemistry / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: PI3K inhibitor; PI3K isoforms; PTEN; PTEN hamartoma tumor syndrome; skin disease