title: Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity.
abstract: Endometrial carcinoma (EC) exhibits the strongest association with obesity of all cancers. Growth of these tumors is driven by PI3K/AKT activation, and opposed by tumor suppressors, including the tuberous sclerosis complex 2 (TSC-2) and p27, with inactivation of TSC2 and loss or cytoplasmic mislocalization of p27 both being linked to PI3K/AKT activation. However, little is known about the involvement of p27 in the development of EC arising in the setting of obesity, especially its role early in disease progression. Using a panel of EC cell lines, in vitro studies using PI3K inhibitors provided evidence that p27 rescue contributes to the efficacy of interventions that inhibit endometrial cell growth. In "at risk" obese patients, and in an animal model of obesity-associated EC (Tsc2-deficient Eker rats), p27 was moderately-to-severely reduced in both "normal" endometrial glands as well as in endometrial complex atypical hyperplasia (obese women), and endometrial hyperplasia (obese rats). In obese Eker rats, an energy balance intervention; caloric restriction from 2-4 months of age, reduced weight, increased adiponectin and lowered leptin to produce a favorable leptin:adiponectin ratio, and reduced circulating insulin levels. Caloric restriction also increased p27 levels, relocalized this tumor suppressor to the nucleus, and significantly decreased hyperplasia incidence. Thus, dietary and pharmacologic interventions that inhibit growth and decrease risk for development of endometrial lesions are associated with increased expression and nuclear (re)localization of p27. These data suggest that p27 levels and localization may be useful as a biomarker, and possible determinant, of risk for EC arising in the setting of obesity.
authors.forename: A S
authors.initials: AS
authors.lastname: McCampbell
authors.forename: M L
authors.initials: ML
authors.lastname: Mittelstadt
authors.forename: R
authors.initials: R
authors.lastname: Dere
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.forename: B
authors.initials: B
authors.lastname: Djordjevic
authors.forename: P T
authors.initials: PT
authors.lastname: Soliman
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: Wei
authors.forename: S D
authors.initials: SD
authors.lastname: Hursting
authors.forename: K H
authors.initials: KH
authors.lastname: Lu
authors.forename: R R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Center for Translational Cancer Research, 2121 W. Holcombe Blvd., Houston, Texas 77030, USA. cwalker@ibt.tamhsc.edu.
authors.forename: C L
authors.initials: CL
authors.lastname: Walker
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D004714:Endometrial Hyperplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012306:Risk; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020738:Leptin; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat