CDB-4124 (
Proellex or
telapristone acetate) is a modulator of
progesterone receptor (PR) signaling, which is currently employed in preclinical studies for prevention and treatment of
breast cancer and has been used in clinical studies for treatment of
uterine fibroids and
endometriosis. Here we provide evidence for its action on
steroid hormone-signaling, cell cycle-regulated genes and in vivo on mammary
carcinogenesis. When
CDB-4124 is given to rats at 200 mg/kg for 24 months, it prevents the development of spontaneous mammary hyperplastic and premalignant lesions. Also,
CDB-4124 given as subcutaneous pellets at two different doses suppressed, dose dependently,
N-methyl-N-nitrosourea (MNU)-induced mammary
carcinogenesis. The high dose (30 mg, over 84 days) increased
tumor latency from 66 ± 24 days to 87 ± 20 days (P < 0.02), decreased incidence from 85% to 35% (P < 0.001), and reduced multiplicity from 3.0 to 1.1
tumors/animal (P < 0.001).
Tumor burden decreased from 2.6 g/animal to 0.26 g/animal (P < 0.01).
CDB-4124 inhibited cell proliferation and induced apoptosis in MNU-induced mammary
tumors, which correlated with a decreased proportion of PR(+)
tumor cells and with decreased serum
progesterone.
CDB-4124 did not affect serum
estradiol. In a mechanistic study employing T47D cells we found that
CDB-4124 suppressed G(1)/G(0)-S transition by inhibiting CDK2 and CDK4 expressions, which correlated with inhibition of
estrogen receptor (ER) expression. Taken together, these data indicate that
CDB-4124 can suppress the development of precancerous lesions and
carcinogen-induced ER(+) mammary
tumors in rats, and may have implications for prevention and treatment of human
breast cancer.