Luminal breast cancers are susceptible to an endocrine therapy. Palbociclib (PALBO), a CDK 4/6 inhibitor, is currently used in combination with endocrine therapy to treat advanced hormone receptor-positive breast cancer (BC). However, with time patients acquire resistance. Therefore, alternative therapies are required to reduce BC mortality. We have recently reported that BC patients with tumors expressing higher levels of isoform A of the progesterone receptor (PRA) than isoform B (PRB) may benefit from an antiprogestin treatment. The aim of this study was to evaluate the effect of PALBO in combination with the antiprogestin mifepristone (MFP) in the T47D BC model. We have already shown that MFP (10 nM) inhibits cells proliferation of T47D and T47D-YA cells (expressing only PRA) but not of T47D-YB cells (expressing only PRB). PALBO (100 nM) inhibited cell proliferation in the three cell lines. The combination of MFP and PALBO induced an additive inhibitory effect only in T47D and T47D-YA cells (p<0.001). To confirm these results in vivo, we inoculated T47D cells into NSG female mice. When the tumors were palpable, mice were treated with PALBO (20 mg/kg sc x 5 days a week) and/or MFP (0.5 mg/pellets; suboptimal dose), or vehicle. Only the drug combination was effective inducing a significant inhibition of tumor growth (p<0.01) confirming the therapeutic potential of this combo. Ongoing studies will unravel the mechanism related with both pathways crosstalk.