We have developed methods to use anticyclin A, B, and E antibodies as reagents to specifically detect proliferating cells in specific phases of the cell cycle in formalin-fixed, paraffin-embedded sections of tissues and cells. Staining of 48 archival cases of breast cancer showed that these antibodies estimate the tumor proliferation fraction and therefore are potentially useful for the prediction of prognosis. A subset of cancers had a high frequency of tumor cells expressing cyclins A and E, out of proportion to other proliferation markers, suggesting that these tumors may have deregulated cyclin expression. In addition to recognizing authentic cyclin E in the nucleus of proliferating cells, anticyclin E antibody cross-reacted with a cytoplasmic protein in nonproliferating endothelial cells. This cross-reaction allows the simultaneous visualization and quantitation of microvessels in the tumors, measuring a second potential predictor of breast cancer prognosis, tumor angiogenesis.Cyclins are proteins that vary in abundance and associate with and activate different cyclin-dependent kinases (cdk) at different stages of the cell cycle, a given cyclin-cdk complex being essential for passage through a specific stage in the cycle. The periodic appearance of the cyclins in distinct phases of the cell cycle suggests that they can be used as markers for proliferation of tissues. Because the three different cyclins mark different phases of the cell cycle-E for G1 and early S, A for S and G2, and B for late G2 (1-3)-the fraction of cells positive for a given cyclin should predict the fraction in a given phase of the cell cycle. Further, increased expression of various cyclins has been noted in extracts of human cancers, cyclin E in particular being markedly elevated in multiple tumors of different origins (4, 5), and an easy method for detecting such tumors will allow their biological behavior to be separately followed in clinical studies. Estimation of the proliferative behavior of a tumor is important for the management and prognosis of breast cancers. After local excision of node-negative tumors, two-thirds of the patients are expected to do well without further adjuvant therapy, and one-third are expected to relapse. Since chemotherapy is most effective before widespread metastases, it is useful to be able to predict which cancers are likely to recur in order to avoid undertreating these patients or overtreating patients whose tumors are not expected to recur (6, 7). One such prognostic factor is the S phase fraction (SPF) of the tumor estimated by fluorescence-activated cell sorting (FACS) analysis for DNA content of singly suspended tumor cells (8-10). Patients with a large fraction of tumor cells in S and G2 have a poorer prognosis and SPF has been used to guide the selection of patients for adjuvant therapy.Despite its value, flow cytometry of breast cancers is not performed widely, mostly because such analyses require fresh, relatively large tumors with enough tumor left over after tissueThe publication ...
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