We have studied the hormonal regulation of the gene encoding Zn-alpha 2-glycoprotein (Zn-alpha 2-gp), a human protein with a high degree of amino acid sequence similarity to class I histocompatibility antigens that is produced by a specific subset of breast carcinomas. Northern blot analysis revealed that dexamethasone and 5 alpha-dihydrotestosterone strongly induced the accumulation of Zn-alpha 2-gp mRNA in T-47D human breast cancer cells. Furthermore, the effect of these two hormones was shown to be additive, since the combination of both hormones produced a stimulation of Zn-alpha 2-gp mRNA of at least 3-fold over that produced by either hormone alone. By contrast, the addition of 5 beta-dihydrotestosterone, 17 beta-estradiol, or progesterone failed to induce the expression of Zn-alpha 2-gp. The stimulatory effect of glucocorticoids and androgens on Zn-alpha 2-gp expression was produced in a time and dose dependent manner, without significantly affecting the cell proliferation rate. A time-course study demonstrated that the induction of Zn-alpha 2-gp mRNA by androgens and glucocorticoids reached a level of 4 or 3.2-fold over the untreated control after seven days of incubation in the presence of a 10(-7) M concentration of 5 alpha-dihydrotestosterone or dexamethasone, respectively. A dose-response study showed that as little as 10(-11) M of 5 alpha-dihydrotestosterone or dexamethasone produced an accumulation of Zn-alpha 2-gp mRNA of 2.4 or 2.1-fold over the control, respectively. On the basis of these results, we propose that Zn-alpha2-gp may be useful as a biochemical marker of breast carcinomas with a specific pattern of hormone responsiveness in whose development glucocorticoids and/or androgens may play a significant role.