LOSS OF BCL-2 IN INVASIVE BREAST-CANCER IS ASSOCIATED WITH HIGH-RATESOF CELL-DEATH, BUT ALSO WITH INCREASED PROLIFERATIVE ACTIVITY

Bcl-2 has been demonstrated to inhibit apoptosis in breast cancer cell s in vitro, and the ratio between Bcl-2 and its proapoptotic homologue Bar seems to be an important determinant of cellular sensitivity to i nduction of apoptosis. However, little information is available on the relationship between Bcl-2 and the rate of apoptotic and necrotic cel l death in breast tumours. From a series of 441 premenopausal, lymphno de-negative breast cancer patients, a subset of 49 tumours was selecte d in which immunostaining for the 26-kDa isoform of Bcl-2 was either a bsent (n = 23) or very high (n = 26). High expression of Bcl-2 was fou nd to be strongly associated with low rates of apoptotic (P < 0.001) a nd necrotic cell death (P < 0.001). The mean value of the apoptotic in dex 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 Bar correlated neither with Bcl-2 nor with the frequency of apoptotic cell s. Immunostaining for the antiapoptotic Bcl-2 homologue Bcl-X-L correl ated with Eel-2 expression (P < 0.001) but not with apoptosis. High pr oliferation rate and high tumour grade (Bloom-Richardson) were strongl y associated with absence of Eel-2 expression (P < 0.001). p53 accumul ation was associated with absence of Bcl-2 expression and increased ap optotic activity. Loss of Bcl-2 expression was strongly correlated wit h increased apoptotic and necrotic cell death, high proliferation rate and high tumour grade, supporting a model in which Eel-2 not only med iates cell death, but also cell division in breast cancer tissue, and in which regulation of cell division and cell death are tightly linked .