Hormonal Risk Modulation in PTEN Mutant Cells

Estrogens and progestins have a reciprocal effect on endometrioid endometrial cancer risk. Epidemiological studies of endometrial cancer risk factors show a 2-10-fold increased cancer risk in women exposed to estrogens without opposing effects of progestins (6,43-45). The protective effects of progestins are evident in women using combined oral contraceptives, as they have a 0.5-0.7 endometrial cancer risk relative to controls (46,47). Risk modulation occurs through interaction of these systemically administered agents with the target endometrial tissue. Identification of a very high baseline frequency of endometrial mutagenic events, such as PTEN-mutated endometrial cells in up to 43% of otherwise normal premenopausal women (latent precancers, discussed earlier) (22), has renewed the focus on endocrine risk modifiers, rather than mutagenesis rates, as the rate limiting event.

Hormonal exposures known to alter endometrial cancer risk probably do so through their activity as positive or negative selection factors for preexisting mutant endometrial clones. A prerequisite for this hypothesis is that latent endometrial precancers and EIN lesions retain hormonal competence. This is the case, as intact estrogen and progesterone

receptors are readily demonstrable in endometrial glands of latent precancers and EIN lesions by immunohistochemistry (22). In order to develop a mechanistic link between hormonal and genetic events during endometrial carcinogenesis, it is necessary to define a point of convergence within affected endometrial cells.

Constitutive PTEN expression by genetically intact, normal endometrial cells is highly elevated by estrogens and reduced progesterone during the normal menstrual cycle (Fig. 5) (48). This is evidence that PTEN, a tumor suppressor gene known to control the rate of cell division, plays a physiological role in the highly mitotic endometrial glands of an estrogen-rich environment, but not in the mitotically quiescent progesterone-dominant postovulatory phase. Consider the fate of a PTEN-mutant clone under varying hormonal conditions. In the presence of unopposed estrogens PTEN-mutant endome-trial glands will proliferate at advantage relative to normal glands, division of which is checked by PTEN. The mutant clone then expands, thereby increasing the likelihood for additional mutation. In contrast, if the same PTEN mutant clone is admixed with PTEN intact normal glands in a progesterone rich environment, cells of neither genotype will require PTEN function, so behave equivalently and without being selective for the mutant population.

Progestin treatment of a type known to reduce endometrial cancer risk causes preferential involution of PTEN-mutant endometrial glands. 83% of latent PTEN-null clones of premenopausal, naturally cycling women with a histologically normal endometrium were present 1 year later (22). There are two implications of this simple observation. First, under hormonally normal circumstances, these cells must be distributed at least in part within the functional reserve of endometrial cells, which regenerate the func-tionalis each month. Second, long-term persistence of PTEN null clones confirms their availability as a target for transient hormonal exposures. In contrast, in women who receive therapeutic doses of progestins only 10% of PTEN-null clones remain after therapy (a 90% involution rate) (49). Ablation of these clones is accompanied by a reduction in endometrial cancer risk.

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