CYCLIN D1 PROTEIN IS OVEREXPRESSED IN HYPERPLASIA AND INTRADUCTAL CARCINOMA OF THE BREAST

The cell cycle regulatory gene cyclin DI is a candidate oncogene in br east cancer, It is overexpressed in 30-50% of invasive primary breast cancers and plays a key role in mediating mitogenic responses to stero ids and growth factors in breast cancer cells in vitro, Because the ro le of cyclin D1 in the proliferative and early noninvasive stages of b reast cancer is largely unknown, we examined normal breast epithelium (NBE), proliferative disease (PD), ductal carcinoma in situ (DCIS), an d invasive carcinoma (IC) to evaluate the timing and possible importan ce of cyclin D1 expression in the development of breast cancer, Using immunohistochemistry, we examined cyclin D1 protein expression in 471 breast tissue samples, A quantitative scoring system for immunohistoch emistry based on percentage of positive cells was developed that corre lated with Western blot analysis of antigen concentration in paired sa mples (r(2) = 0.91, P = 0.003), A sample was considered positive if >5 % of relevant epithelial cells demonstrated nuclear staining, Cyclin D 1 positivity was observed in 11.7% (7 of 60) samples of NBE, 25 % (11 of 44) of PD without atypia, 39.4 % (13 of 33) of atypical ductal hype rplasia, 43.6 % (17 Of 39) Of low-grade DCIS, 47.9% (23 of 48) of high -grade DCIS, and 48.3% (99 of 205) of IC, Cyclin D1 expression was sig nificantly higher in PD than NBE (P = 0.006) and in DCIS than PD (P = 0.038), There was no significant increase from DCIS to IC (P = 0.52), The increase in cyclin D1 expression in the overall progression from N BE to IC was also highly significant (P = 0.0001), Therefore, cyclin D 1 expression was detected at levels significantly greater than in NBE in the earliest proliferative epithelial lesions of the breast with a further significant increase accompanying the progression to any form of cancer, This suggests that overexpression of cyclin D1 protein is i mportant at the earliest stages of breast oncogenesis and continues to have a crucial role throughout the development of malignancy.