Endometrial cancer (EMC) is the most common malignancy of the female genital tract and the fourth most common cancer among American women following breast, lung and colon cancers. Each year, about 40,000 women in the US alone become victims of EMC and about 20% of them die from the disease. The etiology of EMC is not fully understood. Several common genetic alterations are associated with human EMC. The gene with the highest frequency of alteration in EMC is Phosphatase and tensin homolog (Pten). The loss of Pten results in enhanced PISK activity and Akt activation. Increased levels of activated Akt (pAkt) stimulate both cyclooxygenase-2 (Cox2) and mammalian targets of rapamycin complex 1 (mTORCI) activity which are associated with EMC. Cox2 is overexpressed in many solid tumors and Cox2-derived prostaglandins (PGs), especially PGE2 via its receptors EP2/EP4, significantly contribute to carcinogenesis. We have recenfiy shown that levels of pAKT are elevated in Pten-deleted mouse uteri carrying EMC. Our preliminary results also show that mTORCI activity is remarkably upregulated in mouse models of EMC. These observations suggest that Cox2-derived PGs and the mTORCI pathway play significant roles in the development and progression of EMC and inhibiting these pathways may attenuate the incidence and/or virulence of EMC. However, the fact that long-term use of Cox2 inhibitors is associated with increased cardiovascular risks underscores the need for further investigation to circumvent those risks. There is an urgent need to build upon the current knowledge to develop new strategies in which the therapeutic index is improved. Rational combinafions of low doses of these inhibitors offer the potential for improved efficacy with reduced toxicity. Our central theme is to test the hypotheses that Pten deficiency activates PI3K-pAkt-Cox2 and PI3K-pAkt-mT0RC1 pathways that together initiate and promote EMC and targeting both Cox2 and mTORC1 will be synergistic and more effective than either alone in combating EMC. We will test this hypothesis using our newly established mouse model of EMC.
Nearly 40,000 women in the US alone become victims of endometrial cancer (EMC) and about 20% of them die from the disease each year. The etiology of EMC is not clearly understood. The proposed research is aimed at obtaining information to better understand the major cause of the disease and develop new chemopreventive strategies in which the therapeutic index is improved. We will use our newly established mouse model systems relevant to human EMC to address these issues.
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