PTEN is a tumor suppressor: The PTEN tumor suppressor gene is a dual specificity phosphatase located on chromosome 10 (10q23) that acts through an Akt-dependent pathway to suppress cell division ands enable apoptosis (1-3) . Its role in tumor suppression is confirmed by frequent endometrial abnormalities which develop in PTEN-deficient mice (4-6) and high incidence of breast, thyroid, and endometrial cancers in humans with constitutive mutation of one PTEN allele, Cowdens syndrome (7-9).
Nomal Endometrial Expression (above figs.) is hormone dependent: Endometrial gland PTEN expression changes with the hormonal environment during the normal menstrual cycle(10) . Estrogenic conditions (proliferative) produce very high epithelial expression (left panel above). Progesterone exposure during the secretory phase initially creates PTEN-free secretory vacuoles, then progressive depletion of PTEN protein (middle 2 panels, above). PTEN protein eventually disappears from glands, and remains so during menses (right, above). Stromal expression remains high throughout the cycle, but with variation in relative intensity between nuclear and cytoplasmic compartments. If presence of a gene product corresponds to a functional requirement, it might be inferred that under progestin rich conditions of secretory endometrium the tumor suppressive activities of the PTEN protein are unnecessary. This could explain why sporadically occurring PTEN mutations are more likely to progress to carcinoma in women on unopposed estrogens.
Mutant PTEN clones originate in "Normal" Endometrium: 43% of histologically normal proliferative endometrium contain rare glands that have lost the ability to express PTEN protein due to mutation or deletion of the PTEN gene itself (14). These PTEN mutant clones persist between menstrual cycles, providing a reservoir of "first hit" cells over a protracted interval. Since only 2.5% of women will ever get endometrial cancer, progression efficiency of these early stages to carcinoma is highly inefficient. This is the reason that modulaters of progression efficiency (such as hormonal environment, and conditions that change the basal mutation rate) are such strong co-determinants of cancer risk.
in Endometrial Neoplasia:
Mutations and deletions of the PTEN tumor suppressor
gene are the most common genetic change yet found in endometrial adenocarcinoma,
with estimates of the mutational rate ranging from 34-83%
. The highest mutational rates are seen in endometrioid types
of endometrial adenocarcinomas which are preceded by a premalignant lesion
. PTEN mutations are acquired during the premalignant phases of
. Using a subset of tissues from the Endometrial
Precancer Type Collection
, 55% of
computerized morphometry-defined precancerous (EIN, D-Score<0) lesions
were seen to have PTEN mutations.
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