Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice.
BACKGROUND
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.


METHODS
BALB/c mice with subcutaneous 25 mm2 mammary carcinomas expressing estrogen receptor-alpha 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.


RESULTS
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-alpha expression were observed as late events in RU 486-treated and asPR-treated mice with regressing tumors.


CONCLUSIONS
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.
Lamb
Caroline A
CA
Instituto de Biología y Medicina Experimental (Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)), Buenos Aires, Argentina. clamb@dna.uba.ar
Helguero
Luisa A
LA
Giulianelli
Sebastián
S
Soldati
Rocío
R
Vanzulli
Silvia I
SI
Molinolo
Alfredo
A
Lanari
Claudia
C
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D007279:Injections, Subcutaneous; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000502:physiology*
D047628:Estrogen Receptor alpha; D016376:Oligonucleotides, Antisense; D011980:Receptors, Progesterone