Estimation of the proliferative activity of human breast cancer tissue by means of the Ki-67 and MIB-1 antibodies--comparative studies on frozen and paraffin sections

The estimation of the Ki-67 index in human breast cancer tissue has been proven to be a useful prognostic tool. The examination can be performed, however, only on frozen sections (FS). The development of an antibody directed against parts of the Ki-67 antigen (MIB-1) has opened a new route to determine the proliferative activity on paraffin sections (PS). MIB-1 immunohistochemistry is used instead of Ki-67 immunohistochemistry if a tumour is delivered to the pathologist after formalin fixation or if that part of the tissue suspicious for breast cancer must be totally embedded in order to confirm the diagnosis. The present study compares the findings of Ki-67 (FS) and MIB-1 (FS and PS) immunohistochemistry in a total of 544 cases of human breast cancer. The findings confirm a good statistical correlation between the Ki-67 and the MIB-1 findings. The MIB-1 results are 2-2.5 times higher in FS than in PS. Good agreement exists between the Ki-67 indices determined on FS and the MIB-1 indices determined on PS. If the cut-off value for the separation of Ki-67 negative and positive cases is defined as 10%-20%, a MIB-1 index in PS of 10% permits the correct prediction of a negative Ki-67 index in 97% of the cases, and a MIB-1 index of 30% or more correctly predicts a positive Ki-67 index in 90% or more of the cases. Hence, the determination of the MIB-1 index on PS may replace the determination of the Ki-67 index on FS with a high degree of probability.     

Relation of elastosis to biochemical and immunohistochemical steroid receptor findings, Ki-67 and epidermal growth factor receptor (EGFR) immunostaining in invasive ductal breast cancer

We studied 1073 cases of invasive ductal breast cancer, NOS for their elastic content (DEL, ductal+periductal elastosis; TEL, tumour elastosis) and compared the findings with the results of biochemical and immunohistochemical steroid hormone receptor examination. Tumours of patients up to 50 years of age and older were examined separately. In a number of tumours elastosis was also examined in relation to Ki-67 and epidermal growth factor receptor (EGFR) immunostaining. Sensitivity and specificity of DEL and TEL for predicting the receptor, Ki-67 and EGFR findings were estimated. Sensitivity of DEL and TEL for oestrogen and progesterone receptors is dependent on the degree of tumour differentiation and the degree of elastosis, increasing from DEL 1 degree and TEL 1 degree to DEL 3 degrees and TEL 3 degrees. It was more evident in grade 1 (G1) and G2 than in G3 carcinomas. Elastosis is a useful predictor of positive receptor findings particularly in G1 and G2 tumours with moderate and high-grade elastosis. It is a similarly useful predictor of negative receptor values in G3 carcinomas. The predictive value of DEL and TEL for the results of Ki-67 and EGFR immunostaining gradually decreases with increasing elastosis, consistent with the assumption that Ki-67 and EGFR identify the degree of tumour proliferation and invasion, while elastosis correlates with the degree of differentiation of breast cancer. Elastosis is a poor predictor of Ki-67 and EGFR findings in any individual breast cancer. Moderate and high-grade elastosis points to positive steroid hormone receptor assays in G1 and G2 carcinomas. In contrast, the lack of elastosis in G3 carcinomas may indicate a negative receptor assay. Both findings have a high degree of reliability.     

Temporal sequence of mammary intraductal proliferations, ductal carcinomas in situ and adenocarcinomas induced by 1-methyl-1-nitrosourea in rats

An experimental model for mammary carcinogenesis has been described in which intraductal proliferations, ductal carcinomas in situ and adenocarcinomas can be readily detected and the frequency of their occurrence quantified. The objective of the experiment reported in this study was to determine the latency period between carcinogen administration and the occurrence of each of these types of lesion. A total of 150 female Sprague-Dawley rats were injected i.p. with 50 mg 1-methyl-1-nitrosourea (MNU)/kg body wt at 21 days of age. Groups of 30 rats each were killed at 7, 14, 21, 28 and 35 days post-carcinogen. Mammary intraductal proliferations were the first detected lesions and were observed in 20% of the animals at 14 days following carcinogen administration. At 21 days post-carcinogen ductal carcinomas in situ and adenocarcinomas were observed. The number of each type of lesion increased with time post-carcinogen, but the temporal pattern of occurrence was different among lesion types. The pattern of lesion occurrence was consistent with intraductal proliferations being a precursor lesion for ductal carcinomas in situ and adenocarcinomas. Furthermore, the data imply that ductal carcinomas in situ represent one pathway of morphological progression by which intraductal proliferations evolve into invasive carcinomas, but that this lesion type, as currently defined histologically, may not be an obligatory intermediate in morphologic progression. These findings are consistent with emerging evidence of multiple but distinct pathogenetic pathways leading to mammary carcinomas that display different morphological patterns and biological activities.     

The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells

Camptothecin (an inhibitor of topoisomerase I) and etoposide and amsacrine (inhibitors of topoisomerase II) both capable of triggering programmed cell death in Y79 cells, induced a remarkable dose-dependent increase in the level of cyclin E in these cells. Camptothecin was found to be the most effective compound. The effect was not observed when the cells were treated with other inducers of programmed cell death (C2-ceramide, sodium butyrate, interleukin-1beta and tumor necrosis factor), all of which do not damage DNA. The effect, which was completely prevented by inhibitors of macromolecular synthesis, occurred after a lag phase (12 hrs.) and increased concurrently with the rise in programmed cell death (PCD), reaching a maximum after 36 hrs. of incubation, when a large percentage of cells (95%) showed clear PCD signals. We suggest that cyclin E takes part in the final stage of programmed cell death which is induced by topoisomerase inhibitors in Y79 cells.