Therapeutic Implications of Progesterone Receptor-Mediated Regulation of Cell Cycle in Breast Cancer

摘要

Since the 2007 summary report, we have made significant progress in elucidating the novel mechanisms by which PR regulates expression of E2F1, a key regulator of cell cycle progression, in T47D breast cancer cells. In addition to a direct regulatory pathway involving recruitment of PR to the E2F1 promoter, we have identified several indirect modes of regulation. First, ligand-bound PR stimulates increased recruitment of E2F1 to its own promoter in a positive feedback loop. Second, treatment with the synthetic progestin R5020 induces expression of KLF15, a member of the Sp/KLF superfamily of transcription factors, which can then bind to GC-rich DNA within the E2F1 promoter and further amplify transcriptional activation. Finally, we have discovered that lower concentrations of the synthetic progestin R5020 are better able to mediate induction of E2F1 than higher concentrations of R5020. This means that the current paradigm of giving low dose progestins in combination with estrogen in HRT and contraceptives may actually be increasing the activation of certain downstream PR target genes, including those involved in cell cycle progression and proliferation.