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Phosphorylation of human progesterone receptors by MAPKs mediates transcriptional synergy between progestins and MEKK1 in human breast cancer cells
Breast Cancer Research volume 2, Article number: P2.06 (2000)
Breast cancers that are steroid-hormone resistant often overexpress growth factor receptor tyrosine kinases, including members of the type I (EGFR/Erb2) family. Cross-talk between growth factor- and progesterone-mediated signal transduction pathways may contribute to the development of resistance to steroid hormone-based therapies in breast cancer. To mimic constitutive activation of molecules downstream of growth factor signalling pathways, we overexpressed activated MAP/ERK Kinase Kinase (MEKK) in T47D human breast cancer cells. MEKK is a strong activator of p42/p44, and p38 mitogen activated protein kinases (MAPKs). MEKK expression resulted in 20-fold increased R5020-mediated transcription driven by a co-expressed progesterone-response-element (PRE)-containing promoter linked to the luciferase reporter gene; progesterone receptor (PR) levels did not change in the presence of MEKK alone, but decreased in the presence of MEKK and R5020. Potentiation by MEKK of progestin-induced transcription also occurred in HeLa cells, and was dependent on the presence of a PRE, and functional PR. PR antagonists RU486 and ZK98299 blocked this effect. The MEK inhibitor, PD98059, also blocked transcriptional synergy between MEKK and progestins, indicating a requirement for p42 and p44 MAPKs. To test whether the effect of MAPK activation was due to direct phosphorylation of PR, we expressed MEKK in T47D cells stably expressing either wild-type or mutant PR, in which either of two MAPK consensus site serine residues, Ser 294 or Ser 345, were mutated to alanine. Both MAPK mutants of PR were resistant to MEKK- and R5020-induced transcriptional synergy, but, like wild-type PR, still responded to progestins alone. Thus, mutant PR are functional in response to progestins, but are incapable of cross-talk with MAPK-driven pathways. Phosphorylation of PR by MAPKs in response to peptide growth factor signalling may increase PR transcriptional activity on PRE-containing growth regulatory genes, thus altering steroidal control of breast cancer cell growth.
Supported by NIH grant DK-53825.
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Lange, C., Shen, T. & Horwitz, K. Phosphorylation of human progesterone receptors by MAPKs mediates transcriptional synergy between progestins and MEKK1 in human breast cancer cells. Breast Cancer Res 2, P2.06 (2000) doi:10.1186/bcr104
- Progesterone Receptor
- Human Breast Cancer Cell
- Growth Factor Signalling