Lack of cyclin E immunoreactivity in non-malignant breast and association with proliferation in breast cancer

Abstract

Summary Cyclin E is a G, cyclin that is essential for the transition from G, to S phase in the cell cycle. Alterations to cyclin E expression or regulation could be important in tumorigenesis. Previous immunohistochemical and immunoblotting studies have investigated the expression of cyclin E in breast carcinomas. In this study, cyclin E has been investigated in a range of non-malignant and malignant breasj using immunohistochemistry. Normal and benign tissue from pre-and post-menopausal women (39 cases), non-involved tissue from cancercontaining breasts (47 cases), ductal carcinoma in situ (22 cases) and invasive breast carcinomas (109 cases) have been examined. There was no reactivity in any of the non-malignant breast. Only one ductal carcinoma in situ contained more than 5% reactive cells. A total of 28% of invasive carcinomas had > 5% of reactive cells (range 0-88% positive cells, mean 12.59%, median 1.0%). A significant association was found with poorer differentiation (P < 0.001), high MIBl index (P < 0.001), lack of oestrogen receptor (0.05 > P > 0.025) and the presence of p53 protein (0.05 > P > 0.025). Virtually all cases with cyclin E and p53 were poorly differentiated. The presence of cyclin E is therefore only found in breast malignancies and is associated with more aggressive features, including high proliferation.Keywords: breast cancer; normal breast; cyclin E; immunohistochemistry The cell cycle is the ordered set of processes by which one cell grows and divides into two daughter cells (Murray and Hunt, 1993). This process is the basis for the continuity of life and underlies the complexity of growth, renewal and repair active in all multicellular organisms. Over the last two decades, our knowledge of the complex machinery which regulates the cell cycle has dramatically increased; in particular, the links between oncogenesis and the cell cycle components.Transition through the different phases of the cell cycle is achieved by the formation and inhibition of enzymatically active protein complexes composed of cyclins and their regulatory subunits, the cyclin-dependent kinases (CDKs) (Hunter and Pines, 1994). Among the GI cyclins, cyclin E appears to be essential for the G1/S transition as inhibition of the function of cyclin E and its related cyclin-dependent kinase, cdk2, prevents mammalian cells from entering S phase (Pagano et al, 1993;Tsai et al, 1993;Ohtsubo et al, 1995). The cyclin E protein level peaks in late GI (Dulic et al, 1992;Koff et al, 1992), which correlates with the phosphorylation of pRb, the product of the retinoblastoma tumour suppressor gene. pRb plays a critical role in the cell cycle as its phosphorylation leads to the liberation of certain bound transcription factors essential for DNA synthesis (Nevins, 1992;La Thangue, 1994). The importance of cyclin E in the cell cycle suggests that it is a potential target in tumorigenesis.In the search for newer markers which can provide information about breast cancer behaviour, attention has recently focused on the role of cyclin E. P...

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