Regulation of Gene Expression by Progesterone in Cancer Cells: Effects on Cyclin D1, EGFR and VEGF

Progesterone (P4) participates in the regulation of several physiological and pathological processes in mammals through the interaction with its intracellular receptors (PR), which are ligand-dependent transcription factors. Many human cancers depend on P4 for growth and metastasis, especially cancers of reproductive tissues. In women, administration of combined estrogen and progestin hormone replacement therapy for postmenopausal symptoms increases the risk of breast cancer relative to women taking estrogens alone. P4 exerts its actions through various mechanisms classified as classical and non-classical. PR has dual functions as a nuclear transcription factor and as a modulator of cell signaling pathways. Many PR target genes do not contain canonical progesterone response elements (PRE) in their promoter regions and may thus be regulated by PR tethering to other transcription factors and/or rapid signaling, independent of direct PR DNA binding. We review the mechanisms involved in P4 effects on genes implicated in control of cell cycle, proliferation, angiogenesis and metastasis, such as cyclin D1 and epidermal growth factor receptor (EGFR) whose promoters lack PRE sequences, and vascular endothelial growth factor (VEGF) which gene contains PRE in its promoter region. The understanding of the molecular mechanisms involved in the regulation of cyclin D1, EGFR and VEGF expression by P4 will be helpful for the development of new cancer therapies.