Differential expression of p16/p21/p27 and cyclin D1/D3, and their relationships to cell proliferation, apoptosis, and tumour progression in invasive ductal carcinoma of the breast

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Abstract
In order to understand the intricate relationship of cell proliferation and apoptosis in tumour development, proliferation markers (Ki‐67 and c‐myc), apoptosis, cell‐cycle inducers cyclin D1 and D3, and cell‐cycle inhibitors p16INK4, p21CIP1, and p27KIP1 were evaluated in ductal breast carcinoma. The heterogeneous nature of breast tumours provides a system by which the changes in cell‐cycle genes can be explored under a wide range of proliferation and apoptotic indices. To address the above issues, immunohistochemical studies were conducted in 40 pairs of tumours and adjacent normal ductal tissues. The TUNEL method was used to identify apoptotic cells. Except for p27/KIP1, the proliferation (Ki‐67, c‐myc) and the apoptotic indexes together with levels of p16/INK4a, p21/CIP1, cyclin D1, and cyclin D3, were clearly elevated among tumour tissues, while absent in the adjacent normal tissues. Spearman correlation analysis indicated strong associations among apoptotic index, Ki‐67, c‐myc, and tumour grade. In addition, p21/CIP1 and cyclin D3 were positively correlated, while p16/INK4a, p27/KIP1, and cyclin D1 were negatively correlated with tumour grade. There was clear decoupling between p21 and p27, as well as decoupling between cyclin D1 and cyclin D3, in terms of their relationship to cell proliferation and apoptosis, indicating differential roles in tumour progression. Copyright © 2001 John Wiley & Sons, Ltd.