THE ASSOCIATION OF P53 IMMUNOPOSITIVITY WITH TUMOR PROLIFERATION AND OTHER PROGNOSTIC INDICATORS IN BREAST-CANCER

Abnormal accumulation of the p53 tumor suppressor gene product was analyzed in 198 primary invasive human breast carcinomas. In 47 of these cases, single-strand conformational polymorphism was used to detect mutations in the highly conserved exons 5-9 of the gene. Mutations as determined by single-strand conformational polymorphism were found in 15 of 15 strongly immunopositive cases (100%) and 3 of 23 immunonegative cases (13%). There were also nine cases with <1% immunopositive cells (borderline immunopositivity); p53 mutations were detected in seven of these cases. The results suggest that p53 immunopositivity is a highly specific, albeit somewhat insensitive surrogate for p53 mutations. p53 accumulation, detected by immunohistochemical methods using antibody PAb 1801, was noted in 29.8% of the cases and was associated with estrogen receptor (ER) negativity (P = 0.0003), progesterone receptor (PR) negativity (P = 0.008), and high histological grade (P = 0.037) by univariate analysis. Incorporation of bromodeoxyuridine was used to determine the percentage of cells synthesizing DNA (proliferative fraction). When bromodeoxyuridine was administered either in vivo (n = 93) or in vitro (n = 79), p53 accumulation was only marginally related to proliferative fraction (P = 0.067 by chi(2); P = 0.055 by Mann-Whitney). When tumors were segregated by ER status, the aforementioned associations of p53 immunopositivity with PR negativity, high histological grade, and increased proliferation rate lost their significance. p53 accumulation did not correlate with tumor size, clinical stage, axillary node metastases, or age at diagnosis. Three of ten exclusively intraductal carcinomas (two of which were of the comedo type) were immunopositive for p53. There was complete concordance between p53 immunopositivity of primary invasive lesions and concurrent lymph node metastases (24 cases examined). These observations suggest that p53 mutations usually are acquired at a stage in malignant progression prior to invasive carcinoma. Additionally, the fact that immunohistochemistry detected the majority of tumors with p53 mutations suggests that missense mutations leading to an altered gene product, rather than nonsense mutations, are the most frequent form of p53 alterations in breast cancer.