Expression of the retinoblastoma-related gene Rb2/p130 is downregulated inatypical endometrial hyperplasia and adenocarcinoma

The retinoblastoma-related gene Rb2/p130 encodes a protein that is a negati ve cell-cycle regulator normally expressed in a number of adult tissues. Th is protein shares many structural and functional features with the product of the retinoblastoma gene, one of the best-studied tumor-suppressor genes, and plays a fundamental role in growth control. The Rb2/p130 gene product associates with specific members of the E2F family and various cyclins, dis playing a growth-suppressive activity specific for the G(0)/G(1) phases. It has been reported that Rb2/p130 is involved in the pathogenesis and progre ssion of lung cancer and mesothelioma. We previously demonstrated for the f irst time that reduced immunohistochemical expression of Rb2/ p130 was a st rong independent predictor of poor outcome in endometrial cancer. The aim o f the present study,vas to evaluate Rb2/ p130 expression in normal, hyperpl astic, and neoplastic endometrial lesions to determine whether the protein plays a significant role in endometrial carcinogenesis. We evaluated Rb2/p1 30 expression by immunohistochemistry staining in 102 specimens chosen to r epresent a spectrum of endometrial changes, including proliferative endomet rium (n = 18), secretory endometrium (n = 18), simple or complex hyperplasi a without atypia (n = 18), atypical hyperplasia (n = 18), and invasive carc inoma (n = 30). We found that Rb2/p130 was highly expressed in proliferativ e endometrium and in hyperplasia without atypia, the mean percentage of sta ined nuclei being 66% and 60%, respectively, but was downregulated in secre tory endometrial, atypical hyperplasia, and carcinoma, with mean scores of 38%, 25%, and 22%, respectively When categorized on a semiquantitative scal e (negative v 1% to 50% v >50% positivity), endometrial cancer displaced si gnificantly less staining than all other endometrial samples (P <.001). Poo rly differentiated carcinomas (n = 9) showed a significantly lo ic er immun oreactivity for Rb2/p130 than did well-differentiated carcinomas (n = 11; P =.005) and moderately differentiated carcinomas (n = 10; P =.03). In addit ion, atypical hyperplasia showed a significantly lower immunoreactivity tha n either proliferative endometrium (P =.003) or hyperplasia without atypia (P = 0.02). Our findings of a progressive decrease in Rb2/p130 expression f rom hyperplastic endometrium through atypical hyperplasia to poorly differe ntiated carcinomas suggest the involvement of this negative cell-cycle regu lator in endomctrial carcinogenesis. Furthermore, immunostaining for Rb2/p1 30 may prove diagnostically useful in the often difficult distinction betwe en hyperplastic and atypical hyperplastic endometrium.