The Induction of KLF5 Transcription Factor by Progesterone Contributes to Progesterone-induced Breast Cancer Cell Proliferation and Dedifferentiation

Progesterone (Pg) promotes normal breast development during pregnancy and lactation and increases the risk of developing basal-type invasive breast cancer. However, the mechanism of action of Pg has not been fully understood. In this study, we demonstrate that the mRNA and protein expression of Klf5, a pro-proliferation transcription factor in breast cancer, was dramatically up-regulated in mouse pregnant and lactating mammary glands. Pg, but not estrogen and prolactin, induced the expression of Krüpple-like factor 5 (KLF5) in multiple Pg receptor (PR)-positive breast cancer cell lines. Pg induced the KLF5 transcription through PR in the PR-positive T47D breast cancer cells. Pg-activated PR increased the KLF5 promoter activity likely through binding to a Pg response element at the KLF5 promoter. Importantly, Pg failed to promote T47D cell proliferation when the KLF5 induction was blocked by small interfering RNA. KLF5 is essential for Pg to up-regulate the expression of cell cycle genes, including CyclinA, Cdt1, and E2F3. In addition, KLF5 overexpression was sufficient to induce the cytokeratin 5 (CK5) expression, and the induction of CK5 by Pg was significantly reduced by KLF5 small interfering RNA. Consistently, the expression of KLF5 was positively correlated with that of CK5 in a panel of breast cancer cell lines. Taken together, we conclude that KLF5 is a Pg-induced gene that contributes to Pg-mediated breast epithelial cell proliferation and dedifferentiation.