CONICET | Buscador de Institutos y Recursos Humanos

Preclinical data suggests that antiprogestins inhibit the growth of luminal breast carcinomas expressing higher levels of progesterone receptor (PR) isoform A (PRA) than isoform B (PRB). Thus, we conducted a pre-surgical window of opportunity trial to test the effect of mifepristone (MFP; 200 mg, PO, QD, 14 days) in 20 breast cancer patients selected by their high PRA/PRB isoform ratio (MIPRA; NCT02651844). The primary endpoint was to compare the Ki67 levels of biopsies and the post-therapy surgical specimens. A 49.62% decrease in the median was registered in all surgical specimens compared to baseline (p=0.0003). RNA-seq analysis showed that MFP upregulated genes related to the immune system and matrix remodeling, and downregulated genes involved in cell-cycle and proliferative pathways. Now we report data regarding the PR and estrogen receptor alpha (ER) regulation by MFP and plasma levels of MFP and 20 steroid hormones (LC-MS/MS). In western blot studies an enrichment of the PR isoforms in the nuclear compartment with upshifted bands was observed in MFP-treated samples (p = 0.002, Wilcoxon). Immunohistochemical studies comparing pre- and post- treatment samples suggested a decrease in PR, ER, pSer294PR and pSer118ER after treatment. MFP plasma levels were 683.6 +/- 28.6 nM at day 7, and 757.5 +/- 41.7 nM at day 14 after treatment initiation. An expected increase in cortisol levels (p < 0.001) and other steroids was observed in MFP-treated plasma from patients. Our results suggest that MFP is playing an active role regulating target genes in MFP-treated patients. The decrease in pSer294 PR suggest an inhibition in MAPK-mediated activation of PR. Since in a MFP-sensitive mouse model plasma levels of 20 nM are effective inducing tumor regression it may be suggested that lower MFP doses may exert similar therapeutic effects with less antiglucocorticoid side effects