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Molecular and Cellular Biology, January 2007, p. 466-480, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.01539-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Progesterone Receptors Upregulate Wnt-1 To Induce Epidermal Growth Factor Receptor Transactivation and c-Src-Dependent Sustained Activation of Erk1/2 Mitogen-Activated Protein Kinase in Breast Cancer Cells{triangledown}

Emily J. Faivre and Carol A. Lange*

University of Minnesota Cancer Center, Departments of Medicine and Pharmacology, Division of Hematology, Oncology, and Transplantation, 420 Delaware Street SE, MMC 806, Minneapolis, Minnesota 55455

Received 17 August 2006/ Returned for modification 21 September 2006/ Accepted 22 October 2006

Progesterone receptor (PR) ligand binding induces rapid and transient (5- to 10-min) activation of cytosolic c-Src-Ras-Erk1/2 mitogen-activated protein kinase (MAPK) signaling that is independent of PR functioning as transcription factors. Here, we have explored the integration of PR-dependent transcription and rapid signaling events in breast cancer cells. PR-B, but not PR-A, induced robust and sustained (6- to 72-h) Erk1/2 activation that was required for elevated cyclin D1 protein but not mRNA levels. Sustained Erk1/2 activation in response to progestins occurred via a novel mechanism distinct from rapid signaling initiated by PR/c-Src interactions and required the PR-B DNA-binding domain (DBD). PR/progestin upregulated epidermal growth factor receptor (EGFR) and Wnt-1. In response to PR-induced Wnt-1 signaling, matrix metalloprotease (MMP)-mediated membrane-proximal shedding of EGFR ligands transactivated EGFR and induced persistent downstream c-Src and Erk1/2 activities. T47D cell anchorage-independent growth was stimulated by progestins and blocked by inhibition of Erk1/2, c-Src, EGFR, or RNA interference of Wnt-1. Similarly, cell growth in soft agar required the PR DBD but was sensitive to disruption of PR/c-Src interactions, suggesting that both PR-B-induced rapid signaling events and nuclear actions contribute to this response. Our discovery that progestins are capable of robust autocrine activation of EGFR and sustained Erk1/2 signaling provides further support for the physiological linkage of growth factor and steroid hormone signaling. PR-B-induced sustained MAPK signaling may provide prosurvival or proliferative advantages to early breast cancer lesions.

* Corresponding author. Mailing address: University of Minnesota Cancer Center, Departments of Medicine and Pharmacology, Division of Hematology, Oncology, and Transplantation, 420 Delaware Street SE, MMC 806, Minneapolis, MN 55455. Phone: (612) 626-0621. Fax: (612) 626-4915. E-mail: lange047{at}umn.edu.

{triangledown} Published ahead of print on 30 October 2006.

Molecular and Cellular Biology, January 2007, p. 466-480, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.01539-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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