Abstract
Abstract The cyclin dependent kinase (CDK)4/6 inhibitors have been recently approved in combination with endocrine therapy for luminal breast cancer treatment. On the other hand, the use of CDK2 inhibitors, such as Roscovitine, appears as a therapeutic alternative to overcome the acquisition of resistance to CDK4/6 inhibitors. However, there are few clinical trials using CDK2 inhibitors for breast cancer treatment. Most of the reports on the effects of Roscovitine were performed in MCF-7 or MDA-MB-231 cells. The aim of this work was to evaluate the effect of Roscovitine on cell proliferation in T47D human breast cancer cells which express both progesterone receptor (PR) isoforms PRA and PRB, and in the T47D-YA and T47D-YB cell lines expressing only PRA or PRB, respectively. We have previously demonstrated that cells overexpressing PRB showed higher levels of cyclin A as compared with those overexpressing PRA, thus we hypothesized that they would be more sensitive to CDK2 inhibitors. Roscovitine inhibited cell proliferation in a dose dependent manner similarly in both MCF-7 cells (used as positive control) and in T47D cells, with IC50 of 11.99 µM and 11.93 µM respectively. In addition, Roscovitine inhibited cell proliferation induced by estrogen treatment in both cell lines (p<0.01); however the percentage of inhibition was higher in MCF-7 compared with T47D cells (70% versus 50%, respectively; p<0.05). Roscovitine also inhibited cell proliferation induced by the fibroblast growth factor FGF2 in T47D cells (Roscovitine 2 µM p<0.001 and 5 µM p<0.05). Whereas both T47D-YA and -YB cells were similarly inhibited by Roscovitine, only in T47D-YA cells the combination of the antiprogestin mifepristone (MFP; 10 nM) and Roscovitine 1 µM in the presence of FGF2 induced a higher inhibitory effect than MFP or Roscovitine single treatments (p<0.01). We conclude that CDK2 inhibitors may be an option for luminal breast cancer treatment independent of the levels of cyclin A, and that they might be used in combination with antiprogestins only in breast cancer cells overexpressing PRA isoform. Citation Format: Lucía Vottero, Claudia Lanari, Victoria T. Fabris. Effect of Roscovitine and mifepristone in luminal breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5828.
Published Version
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