Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells

Abstract

Medroxyprogesterone acetate (MPA) is a synthetic progestin, currently used in the adjuvant treatment of advanced breast cancer, which induces remission rates (30-40%) comparable to those obtained with other types of endocrine therapies. Since, in addition to its progestin-like action, MPA exhibits androgen- and glucocorticoid-like activities in other tissues, the present study was designed to assess the relative contribution of the different steroid receptor systems in the direct action of MPA on breast cancer cell growth, using the ZR-75-1 human mammary carcinoma cell line as an in vitro model. Unlike pure progestins, MPA potently inhibited the proliferation of ZR-75-1 cells in a concentration-dependent manner either in the presence or in the absence of estrogens, and the addition of insulin had only marginal effects on its growth-inhibitory activity. On the other hand, both hydroxyflutamide (OHF, a non-steroidal monospecific antiandrogen) and RU486 (a potent antiglucocorticoid and antiprogestin also endowed with antiandrogenic activity) competitively reversed MPA antiproliferative effects. MPA further decreased the growth of ZR-75-1 cells co-incubated with maximally inhibitory concentrations of either 5 alpha-dihydrotestosterone (DHT) or dexamethasone (DEX), although at about 300-fold higher MPA concentrations with DHT-treated than with DEX-treated ZR-75-1 cells, thus demonstrating a highly predominant androgenic effect. However, MPA had no effect on the growth of ZR-75-1 cells co-incubated with DHT and DEX simultaneously, thus supporting the predominant role of androgen and glucocorticoid receptors in MPA action. A 12-day preincubation of ZR-75-1 cells with increasing concentrations of MPA (10(-12) to 3 x 10(-6)M) decreased the specific uptake of [3H]estradiol (E2) by intact cell monolayers to the same extent as 10 nM DHT, an effect which was competitively blocked by the addition of OHF (3 microM). MPA action on ZR-75-1 cell growth also significantly differed from that of progestins in being additive to the inhibition of E2-stimulated growth by the steroidal antiestrogen ICI164384. The present data indicate that the main action of MPA on ZR-75-1 human breast cancer cell growth is due to its androgen receptor-mediated inhibitory action, while its glucocorticoid-like activity could play an additional role at high concentrations.

Medroxyprogesterone acetate inhibits interleukin 6 secretion from KPL-4 human breast cancer cells both in vitro and in vivo: a possible mechanism of the anticachectic effect

“…However, only in a recent report has it been suggested that MPA reduces IL-6 secretion from the peripheral blood mononuclear cells of cancer patients (Montovani et al, 1997). MPA is known to bind not only to progesterone receptors but also to glucocorticoid and androgen receptors (Poulin et al, 1989;Narita et al, 1995) Because KPL-4 cells used in this study do not express either oestrogen or progesterone receptors, it is conceivable that MPA may act as a glucocorticoid or androgen through glucocorticoid or androgen receptors. Our preliminary results suggest that hydrocortisone also reduces both basal and TNF-α-stimulated IL-6 secretion from KPL-4 cells (unpublished data).…”

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dΔ12,14,PGJ2

“…Thus, a challenge for future study is to elucidate this mechanism. Other known targets of MPA include glucocorticoid, androgen and progesterone receptors [40][41][42] but control experiments using ligands and antagonists of these receptors failed to mimic or abrogate the effect of MPA on CLL cells, therefore it is unlikely that these are the targets (data not shown). Others have identified that MPA enhances anthracyclin uptake by CLL cells and increases apoptosis of cultured CLL cells exposed to the anthracyclin idarubicin.…”

Polymorphism in the Androgen Receptor and Mammographic Density in Women Taking and Not Taking Estrogen and Progestin Therapy

“…Ligands that bind AR with high affinity include not only testosterone and dihydrotestosterone, but also progestins (24). Human clinical data suggest that the AR may mediate the antiproliferative effects of high-dose synthetic progestins such as medroxyprogesterone acetate on breast cancer cells.…”