Cellular apoptosis susceptibility gene expression in endometrial carcinoma: Correlation with Bcl-2, Bax, and caspase-3 expression and outcome

Deregulation of proliferation and apoptosis is known to contribute to neopl astic transformation and growth. Using specific antibodies for the cellular apoptosis susceptibility (CAS) gene, caspase-3, Bcl-2, and Bax, we examine d the protein expression in 89 endometrial carcinomas and in 56 samples of nonneoplastic adjacent endometrium for comparison. Immunostaining results w ere scored with regard to approximate percentage of positive tumor cells (< 10%, 10% to 50%, > 50%) and relative immunostaining intensity (1+, 2+, 3+) . In nonneoplastic endometrium, CAS protein was expressed in 70.6%, Bax in 64%, caspase-3 in 52%, and Bcl-2 in 87%. In neoplastic tissue, CAS was pres ent in 93% of the tumors, Bax in 88%, caspase-3 in 77%, and Bcl-2 in 51%. B cl-2:Bax ratio was >1 in 9 cases (10%). In cases of atrophy (n=24) and simp le (n=10) and complex (n=22) hyperplasia in the adjacent endometrium, lower levels of expression compared with carcinoma were observed for CAS (p=0.00 3), caspase-3 (p=0.034), and Bax (p=0.04) and higher levels for Bcl-2, alth ough for this protein the results were not statistically significant (p=0.3 2). There was no association between immunoscores and FIGO stage. High casp ase-3 levels were seen in endometrioid tumor type (p=0.017). CAS expression was higher in grade 3 tumors (p=0.002) and older patients (p=0.013). All t umors of younger patients (< 50 years) were Bcl-2 negative (p=0.037). Caspa se-3 correlated positively with CAS (p=0.008), Bax (p=0.04), and low Bcl-2: Bax ratio (p=0.043), and inversely (as a trend) with Bcl-2 (p=0.056). Survi val analysis (Kaplan-Meier and Cox regression) established a strong associa tion between prognosis and stage, grade, and histologic type (all p less th an or equal to0.0036). In addition, shorter survival was observed for patie nts whose tumors contained >50% of positive cells for caspase-3 (p=0.024) o r for CAS (p=0.04). Age, Bcl-2, Bax, and Bcl-2:Bax ratio did not provide pr ognostic information. Our results suggest a role of CAS, Bcl-2, Bax, and ca spase-3, which are apparently involved in the progressive deregulation of p roliferation and apoptosis leading from simple and complex hyperplasia to c arcinoma. In addition, CAS and caspase-3 protein levels may be useful marke rs in predicting the outcome of the patients.