Most
breast carcinomas that are
estrogen receptor (ER) and
progesterone receptor (PR) positive respond initially to an endocrine
therapy, but over time, they develop resistance (acquired
hormone resistance). Others, however, fail to respond from the beginning (constitutive resistance). Overcoming
hormone resistance is one of the major desirable aims in
breast cancer treatment. Using the
medroxyprogesterone acetate (MPA)-induced
breast cancer mouse model, we have previously demonstrated that antiprogestin-responsive
tumors show a higher expression level of PR
isoform A (PRA) than PR
isoform B (PRB), while
tumors with constitutive or acquired resistance show a higher expression level of PRB. The aim of this study was to investigate whether PRA silencing in resistant
tumors was due to PRA methylation. The CpG islands located in the PRA promoter and the first exon were studied by methylation-specific PCR (MSP) in six different
tumors: two antiprogestin-responsive, two constitutive-resistant, and two with acquired resistance. Only in constitutive-resistant
tumors, PRA expression was silenced by DNA methylation. Next, we evaluated the effect of a demethylating agent,
5-aza-2'-deoxycytidine, on PRA expression and antiprogestin responsiveness. In constitutive-resistant
tumors,
5-aza-2'-deoxycytidine treatment in vitro and in vivo restored PRA expression and antiprogestin
RU-486 responsiveness. Furthermore, high levels of
DNA methyltransferase (Dnmts) 1 and 3b were detected in these
tumors. In conclusion, our results suggest that
methyltransferase inhibitors in combination with antiprogestins may be effective in the treatment of constitutive-resistant
carcinomas with a high
DNA methyltransferase level.