Phosphorylated, SUMO-Deficient, Progesterone Receptors Regulate Transcriptional Activity via Targeting Selected Promoters in Breast Cancer Cells
Progesterone receptors (PRs) mediate proliferation in developing mammary tissue and contribute to breast cancer progression. Elevated expression and activity of epidermal growth factor (EGF) receptor family members frequently occur in advanced breast cancer and these receptors undergo extensive cross-talk with PR signaling. Growth factor-induced kinases regulate PR post-translational modification, such as phosphorylation, ubiquitination, and sumoylation. These researchers previously showed that PR-B, but not PR-A, Ser294 phosphorylation occurs in response to EGF treatment or expression of activated downstream protein kinases. PR Ser294 phosphorylation antagonizes sumoylation of PR at Lys388, resulting in derepression/up-regulation of selected PR target genes. They hypothesize that sumoylated-PR recruits co-repressor molecules to the promoters of PR target genes and inhibits transcription. Their studies suggest that in this context, PRs are hyperactive at selected promoters, but also rapidly turn over and may be difficult to detect. This work provides a rationale for targeting growth factor receptor signaling pathways in combination with steroid hormone receptors, including PRs, even when their expression appears low.
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