Elucidation of the Mechanisms by which the Progesterone Receptor Inhibits Inflammatory Responses in Cellular Models of Breast Cancer

Both pro- and anti-mitogenic activities have been ascribed to progesterone receptor (PR) agonists and antagonists in breast cancer cells, however, the transcriptional responses that underlie these paradoxical functions are not apparent. Using non-transformed, normal human mammary epithelial cells (hMECs) engineered to express PR, and standard microarray technology, we defined 2,370 genes that were significantly regulated by the PR agonist R5020. Gene Ontology (GO) analysis revealed that GO-terms involved in inflammation and NF-B signaling were among the most significantly regulated. Interestingly, on those NF-B responsive genes that were inhibited by agonist-activated PR, antagonists either (a) mimicked the actions of agonists or (b) reversed the inhibitory actions of agonists. This difference in pharmacological response could be attributed to the fact that although agonist and antagonist-activated PR is recruited to the promoters of NF-B responsive promoters, the physical presence of PR tethered to the promoter of some genes is sufficient for transcriptional inhibition whereas on others an agonist-activated PR conformation is required for inhibition of NF-B signaling. Importantly, the actions of PR on the latter class of genes were reversed by an AF-2 inhibiting, LXXLL-containing peptide. Consideration of the relative activities of these distinct anti-inflammatory pathways in breast cancer may be instructive with respect to the likely therapeutic activity of PR agonists or antagonists in the treatment of breast cancer.

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Kobayashi S, Stice JP, Kazmin D, Wittmann BM, Kimbrel EA, Edwards DP, Chang CY, McDonnell DP