G1-S transition defects occur in most breast cancers and predict outcome

Cell cycle deregulation is frequently observed in tumors and has moreover b een proposed to be a requirement for tumor development. By analyzing the ex pression of p27 by immunohistochemistry in 100 primary breast tumors and co mbining the analyses with our earlier characterization of cyclin E, D1, p16 , and the retinoblastoma protein (pRB), we have been able to cover the majo rity of potential G1-S transition defects and observed that 90% of the tumo rs had alterations in one or several cell cycle regulatory proteins. Consid erable variations in protein levels were found among tumors, with low p16 e xpression as the most common alteration followed by cyclin E or cyclin D1 o verexpression, low p27 expression or pRB inactivation in decreasing prevale nce. Tumors were grouped according to observed combinations of defects and the proliferative capacity was determined for each group by analyzing Ki-67 labeling index. Low proliferation was observed in tumors with: low p16; hi gh cyclin D1 with normal or high p16 expression; and in tumors without cell cycle defects. Tumors with high cyclin E/low p27 or pRB defects showed hig her proliferation. The survival differed noticeably for patients with vario us combinations of cell cycle defects, and four distinctive clusters were i dentified showing significantly different breast cancer specific survival ( p < 0.0001) for both node-positive (p = 0.0006) and node-negative patients (p < 0.0001). In summary, we have shown that G1-S transition defects are ne arly obligatory in breast tumors and that the specific type of cell cycle d efect influences the clinical behavior of the tumor.