HORMONAL-REGULATION OF THE HUMAN PEPSINOGEN-C GENE IN BREAST-CANCER CELLS - IDENTIFICATION OF A CIS-ACTING ELEMENT MEDIATING ITS INDUCTION BY ANDROGENS, GLUCOCORTICOIDS, AND PROGESTERONE

Pepsinogen C is an aspartic proteinase mainly involved in the digestio n of proteins in the stomach, which is also synthesized by certain hum an breast tumors. To examine the possibility that extragastric product ion of this proteolytic enzyme could be mediated by hormonal factors, we have analyzed pepsinogen C gene expression in human breast cancer c ells subjected to different hormonal treatments. Northern blot analyse s revealed the expression of pepsinogen C gene by T-47D breast cancer cells after induction with dihydrotestosterone, dexamethasone, and pro gesterone but not with estradiol, retinoic acid, or ethanol. Reverse t ranscription-polymerase chain reaction analysis in a series of breast cancer cell lines confirmed the amplification of pepsinogen C mRNA aft er induction with dihydrotestosterone, in those cells expressing the a ndrogen receptor mRNA. The promoter region of the pepsinogen C gene wa s functionally characterized by transient expression of a vector conta ining the promoter region cloned in front of the chloramphenicol acety ltransferase (CAT) reporter gene. CAT activity in T 47D cells was stim ulated in the presence of dihydrotestosterone, dexamethasone, and prog esterone but not by estradiol. By further deletion mapping of the peps inogen C promoter, a minimal region (AGAACTattTGTTCC) was identified a s being responsible for glucocorticoid, androgen-, and progesterone-re gulated gene expression.