Loss of Bcl-2 in invasive breast cancer is associated with high rates of cell death, but also with increased proliferative activity

• Published in: British journal of cancer Vol. 77; no. 5; pp. 789 - 796
• Main Authors: VAN SLOOTEN, H.-J, VAN DE VIJVER, M. J, VAN DE VELDE, C. J. H, VAN DIERENDONCK, J. H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-03-1998
• Subjects: Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Division; Female; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Gynecology. Andrology. Obstetrics; Humans; Ki-67 Antigen - analysis; Mammary gland diseases; Medical sciences; Necrosis; Neoplasm Proteins - analysis; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Premenopause; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins c-bcl-2 - analysis; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Receptors, Estrogen - analysis; Tumors; Human; Cell proliferation; Cell nucleus; Malignant tumor; Gene expression; Antigen; Mammary gland diseases; Cell death; C-Onc gene; Mammary gland; Protooncogene; Apoptosis; High malignancy
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.1998.128

Bcl-2 has been demonstrated to inhibit apoptosis in breast cancer cells in vitro, and the ratio between Bcl-2 and its proapoptotic homologue Bax seems to be an important determinant of cellular sensitivity to induction of apoptosis. However, little information is available on the relationship between Bcl-2 and the rate of apoptotic and necrotic cell death in breast tumours. From a series of 441 premenopausal, lymphnode-negative breast cancer patients, a subset of 49 tumours was selected in which immunostaining for the 26-kDa isoform of Bcl-2 was either absent (n = 23) or very high (n = 26). High expression of Bcl-2 was found to be strongly associated with low rates of apoptotic (P < 0.001) and necrotic cell death (P < 0.001). The mean value of the apoptotic index was 2.69%+/-1.40% in Bcl-2-negative tumours and 0.68%+/-1.00% in Bcl-2-positive tumours. Expression of the proapoptotic protein Bax correlated neither with Bcl-2 nor with the frequency of apoptotic cells. Immunostaining for the antiapoptotic Bcl-2 homologue BcI-X(L) correlated with Bcl-2 expression (P < 0.001) but not with apoptosis. High proliferation rate and high tumour grade (Bloom-Richardson) were strongly associated with absence of Bcl-2 expression (P< 0.001). p53 accumulation was associated with absence of Bcl-2 expression and increased apoptotic activity. Loss of Bcl-2 expression was strongly correlated with increased apoptotic and necrotic cell death, high proliferation rate and high tumour grade, supporting a model in which Bcl-2 not only mediates cell death, but also cell division in breast cancer tissue, and in which regulation of cell division and cell death are tightly linked.