Abnormal expression of cell cycle regulatory proteins in ductal and lobular carcinomas of the breast

In a previous study, we demonstrated that the G1 cell cycle checkpoint in c arcinomas of the breast is frequently abrogated by loss of p16, the product of the CDKN2/INK4A gene, and, to a lesser extent, by loss of pRB, the prod uct of the retinoblastoma gene. The purpose of the present study was to det ermine whether other mechanisms of cell cycle deregulation exist in breast cancers which have retained RE and pie function. Paraffin sections of 81 in vasive breast carcinomas (49 ductal, 26 lobular, 6 mixed) were reacted with monoclonal antibodies against cyclin D1 and p53, using optimized immunohis tochemical staining protocols. The staining results were correlated with th e expression of pie and pRB, and with a variety of pathological parameters and DNA ploidy. Twenty-five tumors (31%) accumulated (presumably mutant) p5 3 and 28 (35%) overexpressed cyclin D1; 7 carcinomas (not including any pur e lobular cancers) abnormally expressed both proteins, p53 accumulation cor related with nuclear, mitotic, and overall grade, but not with tumor size, lymph node involvement, or DNA ploidy. Overexpression of cyclin D1 was not associated with any of the patho-biological variables. There was an inverse correlation between loss of pie and high levels of p53, but not cyclin D1. The G1 cell cycle checkpoint, which is controlled by RE, cyclin D1, and pi e, was abrogated in 65% of carcinomas, and only p53 was abnormal in an addi tional 17%. The number of abnormally expressed genes correlated with mitoti c activity and overall tumor grade, but not with tumor histology, size, or nodal status, suggesting that cell cycle deregulation is an early event in breast tumorigenesis. Only 18% of the carcinomas showed a normal level of e xpression of the four genes tested, and p16 appeared to be the most common target of cell cycle deregulation. These data point to the importance of ce ll cycle regulatory protein abnormalities in human breast cancer.