GLUCOCORTICOIDS AND ANDROGENS UP-REGULATE THE ZN-ALPHA(2)-GLYCOPROTEIN MESSENGER-RNA IN HUMAN BREAST-CANCER CELLS

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 o f amino acid sequence similarity to class I histocompatibility antigen s that is produced by a specific subset of breast carcinomas. Northern blot analysis revealed that dexamethasone and 5 alpha-dihydrotestoste rone strongly induced the accumulation of Zn-alpha(2)-gp mRNA in T-47D human breast cancer cells. Furthermore, the effect of these two hormo nes was shown to be additive, since the combination of both hormones p roduced a stimulation of Zn-alpha(2)-gp mRNA of at least 3-fold over t hat produced by either hormone alone. By contrast, the addition of 5 b eta-dihydrotestosterone, 17 beta-estradiol, or progesterone failed to induce the expression of Zn-alpha(2)-gp. The stimulatory effect of glu cocorticoids and androgens on Zn-alpha(2)-gp expression was produced i n a time and dose dependent manner, without significantly affecting th e cell proliferation rate. A time-course study demonstrated that the i nduction of Zn-alpha(2)-gp mRNA by androgens and glucocorticoids reach ed a level of 4 or 3.2-fold over the untreated control after seven day s of incubation in the presence of a 10(-7) M concentration of 5 alpha -dihydrotestosterone or dexamethasone, respectively. A dose-response s tudy 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 r esults, we propose that Zn-alpha(2)-gp may be useful as a biochemical marker of breast carcinomas with a specific pattern of hormone respons iveness in whose development glucocorticoids and/or androgens may play a significant role.