Immunocytochemical localization of BCL‐2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy

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Abstract
The protein product of the bcl‐2 gene is thought to be involved in inhibition of apoptosis; it may therefore be important in the modulation of hormonal/anti‐hormonal responsiveness exhibited by tumours. This study immunocytochemically investigates (i) relationships between bcl‐2 protein expression in primary breast cancers and other markers of prognostic and therapeutic value and (ii) associations of the bcl‐2 protein with breast cancer responsiveness to endocrine therapy. The bcl‐2 protein was found within the tumour epithelial cell cytoplasm of 32/46 breast cancer specimens; inter‐patient staining was heterogeneous. Immunostaining for steroid hormone receptors was strongly associated with that for the bcl‐2 protein, and it is thus possible that this protein, like progesterone receptor, is under oestrogen regulation via oestrogen receptor. The protein was inversely related to 2 markers of endocrine insensitivity, epidermal growth factor receptor (EGFR) and c‐erbB‐2 oncoprotein, while no associations were observed with either transforming growth factor (TGF)‐alpha or Ki‐67 proliferative status. A highly significant relationship was observed between response to endocrine therapy and the presence of bcl‐2 protein. Indeed, bcl‐2 immunostaining proved to be a more accurate predictor of response than oestrogen receptor status. Patients with elevated bcl‐2 immunostaining (particularly those who co‐expressed high oestrogen receptor levels) appeared to derive the greatest benefit from endocrine therapy. Our results are paradoxical since it was expected that the bcl‐2 protein would counteract the tumour inhibitory effects of endocrine therapies as it is thought to prevent programmed cell death.