ANTISENSE OLIGONUCLEOTIDES TARGETING THE PROGESTERONE RECEPTOR INHIBIT HORMONE-INDEPENDENT BREAST CANCER GROWTH IN MICE

CAROLINE A LAMB; LUISA A HELGUERO; SEBASTIÁN GIULIANELLI; ROCÍO SOLDATI; SILVIA I VANZULLI; ALFREDO MOLINOLO; CLAUDIA LANARI

Breast Cancer Research

BIOMED CENTRAL LTD

Año: 2005 vol. 7 p. 1111 - 1121

1465-5411

Previous data from our laboratory suggested that progesterone receptors (PRs) are involved in progestin independent growth of mammary carcinomas. To investigate this possibility further, we studied the effects of PR antisense oligodeoxynucleotides (asPR) on in vivo tumor growth. BALB/c mice with subcutaneous 25 mm2 mammary carcinomas expressing estrogen receptor-á and PR were either injected intraperitoneally with 1 mg asPR every 24 or 12 hours for 5–10 days, or subcutaneously with RU 486 (6.5 mg/kg body weight) every 24 hours. Control mice received vehicle or scPR. Significant inhibition of tumor growth as well as a significant decrease in bromodeoxyuridine uptake was observed in asPR-treated mice, which correlated with histological signs of regression and increased apoptosis. Mice treated with RU 486 experienced almost complete tumor regression. No differences were detected between vehicle-treated and scPR-treated mice. Anti-progestin-treated and asPR-treated mice were in a continuous estrous/meta-estrous state. Decreased phosphorylated extracellular signal-regulated kinase (ERK)1 and ERK2 levels and estrogen receptor-á expression were observed as late events in RU 486-treated and asPR-treated mice with regressing tumors. We demonstrate, for the first time, inhibition of tumor growth in vivo using asPR. Our results provide further evidence for a critical and hierarchical role of the PR pathway in mammary carcinomas.