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

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 p16(INK4), p21(CIP1), and p27(KIP1) were evaluated in ductal breast carcino ma. The heterogeneous nature of breast tumours provides a system by which t he changes in cell-cycle genes can be explored under a wide range of prolif eration and apoptotic indices. To address the above issues, immunohistochem ical studies were conducted in 40 pairs of tumours and adjacent normal duct al tissues. The TUNEL method was used to identify apoptotic cells. Except f or p27/KIP1, the proliferation (Ki-67, c-myc) and the apoptotic indexes tog ether with levels of p16/INK4a, p21/CIP1, cyclin D1, and cyclin D3, were cl early elevated among tumour tissues, while absent in the adjacent normal ti ssues. Spearman correlation analysis indicated strong associations among ap optotic index, Ki-67, c-myc, and tumour grade. In addition, p21/CIP1 and cy clin D3 were positively correlated, while p16/INK4a, p27/KIP1, and cyclin D 1 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, indica ting differential roles in tumour progression. Copyright (C) 2001 John Wile y & Sons, Ltd.