RU486 is a potent inhibitor of aromatase induction in human breast adipose tissue stromal cells.

Abstract

Aromatization of circulating androgens in adipose tissue is a major source of estrogens in postmenopausal women. As part of our efforts to elucidate the mechanism of aromatase induction in human breast adipose tissue, we tested the effects of the antiglucocorticoid and antiprogestin, RU486, on aromatase induction in primary cultures of adipose tissue stromal cells in a serum-free system devoid of phenol-red. Under these conditions 1 microM cortisol alone induces low levels of aromatase activity within one day, whereas platelet-derived growth factor BB (PDGF) potentiates this effect two- to three-fold. The well-known strong inductive effect of dibutyryl-cAMP (db-cAMP) is also augmented by cortisol, but is inhibited by PDGF in the absence of cortisol. RU486 completely prevented aromatase induction by cortisol and PDGF. Induction by db-cAMP in the presence and absence of cortisol was significantly inhibited by RU486. Even lower activities were measured when RU486 was added to cells stimulated with PDGF and db-cAMP in the absence or presence of cortisol. Similar results were obtained after prolonged incubation. The inhibitory effects of RU486 are dose dependent, less than 1 microM completely blocking the effects of cortisol, whereas 10 microM are needed to block db-cAMP induction. RU486 does not affect cell number, cellular protein, viability or house-keeping enzymes such as lactate dehydrogenase (LDH), and therefore seems to act specifically. The time course of RU486 action on the db-cAMP induction of aromatase indicates that it acts via a newly synthetized mediator or target in stromal cells. These results suggest that all known inducers of aromatase in adipose tissue depend upon the action of signalling molecules (probably members of the nuclear receptor superfamily) which can be blocked by RU486. The inhibitory action of PDGF seems to be independent of steroid hormone action, as seems some basal activity induced by db-cAMP. In conclusion, this in vitro study suggests that RU486 might be a useful tool for the therapy of estrogen-dependent tumours through its inhibition of aromatase induction.