Lucía Vottero¹, Claudia Lanari¹, Victoria Teresa Fabris¹
The use of CDK2 inhibitors, such as Roscovitine (ROSCO), appears as a therapeutic alternative to overcome the acquisition of resistance to Palbociclib in luminal breast cancer. The aim of this work was to evaluate the effect of ROSCO on cell proliferation in cells differing in their progesterone receptor (PR) isoform context. We have already demonstrated that T47D-YB human breast cancer cells (only expressing isoform B; PRB) had increased cyclin A levels compared to T47D-YA cells (only expressing isoform A; PRA). We decided to evaluate if cells overexpressing PRB would be more sensitive to CDK2 inhibitors than those overexpressing PRA. T47D, T47D-YA or T47D-YB cells were treated with FGF2 to increase cell proliferation and then they were treated with ROSCO 2 µM. All cells were similarly inhibited by ROSCO (P< 0.01) and this was accompanied by a decrease in the levels of phospho-ERK. When FGF2-treated cells were incubated with ROSCO 1 µM and/or the antiprogestin mifepristone (MFP; 10 nM), only in T47D-YA cells the combined treatment showed significant inhibitory effects on cell proliferation that were stronger than those induced by the single treatments (P< 0.01). These results suggest that the levels of cyclin A are not a biomarker of CDK2 inhibitor responsiveness. In addition, we show that CDK2 inhibitors may be an option for luminal breast cancer cells overexpressing PRA isoform in combination with antiprogestins.