G. Dran et al., EFFECT OF MEDROXYPROGESTERONE ACETATE (MPA) AND SERUM FACTORS ON CELL-PROLIFERATION IN PRIMARY CULTURES OF AN MPA-INDUCED MAMMARY ADENOCARCINOMA, Breast cancer research and treatment, 35(2), 1995, pp. 173-186
The effect of progesterone (Pg), medroxyprogesterone acetate (MPA), es
tradiol (E(2)), dihydrotestosterone (DHT) and dexamethasone (DEXA) was
studied on the in vitro growth rate of a progestin-dependent (PD), es
trogen-sensitive mammary tumor line originated in an MPA-treated BALB/
c mouse (C4-HD), and on its estrogen-resistant variant (C4-HDR). The s
pecificity of hormone action was further investigated using the anti-h
ormones RU-486 and hydroxyflutamide (FLU). Cell growth was evaluated i
n epithelial and fibroblast-enriched cultures using H-3-thymidine and/
or autoradiography and immunocytochemistry. The results indicate that
cell growth is directly stimulated by MPA and Pg at concentrations ran
ging from 10(-11) to 10(-7) M. RU486 prevented MPA-induced stimulation
in concentrations 10 to 100 fold lower than those of MPA. When used a
lone, it inhibited cell proliferation only in concentrations higher th
an 10(-11)M. At nM concentrations, neither DEXA nor DHT stimulated H-3
-thymidine uptake except DEXA at 100 nM. MPA-induced stimulation was n
ot reverted by micromolar concentrations of FLU. As for E(2) (10(-7)-1
0(-9) M) it prevented MPA stimulation only in cultures of estrogen-sen
sitive tumors. Progesterone receptors (PR) (475 +/- 115 fmoles/10(5) c
ells, n = 5) and estrogen receptors (ER) (ND-115 fmoles/10(5) cells, n
= 5) were detected only in epithelial-enriched cultures. Serum from 7
day-MPA-treated mice induced a significant increase of H-3-thymidine
uptake; an increase was also obtained with serum from untreated ovarie
ctomized animals to which 1 nM-100 nM concentrations of MPA had been a
dded. The stimulatory effect of the exogenous MPA was much lower than
that of the serum obtained from MPA-treated animals. It is concluded t
hat MPA stimulates cell growth of primary cultures of MPA-induced PD t
umors via PR. The results provide support for a direct effect of MPA w
hich may be mediated or potentiated by serum factors.