| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Medicine (Division of Hematology, Oncology, and Transplantation) and Pharmacology, University of Minnesota Cancer Center, Minneapolis, Minnesota 55455
Address all correspondence and requests for reprints to: Carol A. Lange, Departments of Medicine (Division of Hematology, Oncology, and Transplantation) and Pharmacology, University of Minnesota Cancer Center, MMC 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455. E-mail: Lange047{at}umn.edu.
Progestins induce proliferation of breast cancer cells and are implicated in the development of breast cancer. The effects of progestins are mediated by progesterone receptors (PRs), although it is unclear whether proliferative effects are delivered through activities as ligand-activated transcription factors or via activation of cytoplasmic kinases. We report that progestin induces S phase entry of T47D cells stably expressing either wild-type (wt) PR-B or a transcriptionally impaired PR-B harboring a point mutation at Ser294, a ligand-dependent and MAPK consensus phosphorylation site (S294A). Both wt and S294A PR are capable of activating p42/p44 MAPKs and promoting proliferation. However, cells expressing wt, but not S294A PR, exhibited enhanced proliferation in response to combined epidermal growth factor and progestin. S phase progression correlated with up-regulation of cyclin D1. The PR antagonist RU486 also induced MAPK activation, increased cyclin D1 expression, and stimulated S phase entry, which was blocked by inhibition of either p42/p44 or p38 MAPKs, whereas proliferation induced by R5020 was sensitive only to p42/p44 MAPK inhibition. MCF-7 cells stably expressing a mutant PR unable to bind c-Src and activate MAPK failed to support progestin-induced proliferation. These data suggest that PR mediate cell cycle progression primarily through activation of cytoplasmic kinases and independently of direct regulation of transcription, whereas the coordinate regulation of both aspects of PR action are required for enhanced proliferation in response to progestins in the presence of growth factors. Targeting the ability of steroid receptors to activate MAPKs may be beneficial for breast cancer patients.
NURSA Molecule Pages Link:
This article has been cited by other articles:
 |
|
 |
|
  E. J. Faivre, A. R. Daniel, C. J. Hillard, and C. A. Lange Progesterone Receptor Rapid Signaling Mediates Serine 345 Phosphorylation and Tethering to Specificity Protein 1 Transcription Factors Mol. Endocrinol., April 1, 2008; 22(4): 823 - 837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Hammes and E. R. Levin Extranuclear Steroid Receptors: Nature and Actions Endocr. Rev., December 1, 2007; 28(7): 726 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. McGowan, A. J. Russell, V. Boonyaratanakornkit, D. N. Saunders, G. M. Lehrbach, C. M. Sergio, E. A. Musgrove, D. P. Edwards, and R. L. Sutherland Progestins Reinitiate Cell Cycle Progression in Antiestrogen-Arrested Breast Cancer Cells through the B-Isoform of Progesterone Receptor Cancer Res., September 15, 2007; 67(18): 8942 - 8951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. Kesler, D. Gioeli, M. R. Conaway, M. J. Weber, and B. M. Paschal Subcellular Localization Modulates Activation Function 1 Domain Phosphorylation in the Androgen Receptor Mol. Endocrinol., September 1, 2007; 21(9): 2071 - 2084. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Pedram, M. Razandi, R. C. A. Sainson, J. K. Kim, C. C. Hughes, and E. R. Levin A Conserved Mechanism for Steroid Receptor Translocation to the Plasma Membrane J. Biol. Chem., August 3, 2007; 282(31): 22278 - 22288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Carnevale, C. J. Proietti, M. Salatino, A. Urtreger, G. Peluffo, D. P. Edwards, V. Boonyaratanakornkit, E. H. Charreau, E. B. de Kier Joffe, R. Schillaci, et al. Progestin Effects on Breast Cancer Cell Proliferation, Proteases Activation, and in Vivo Development of Metastatic Phenotype All Depend on Progesterone Receptor Capacity to Activate Cytoplasmic Signaling Pathways Mol. Endocrinol., June 1, 2007; 21(6): 1335 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Boonyaratanakornkit, E. McGowan, L. Sherman, M. A. Mancini, B. J. Cheskis, and D. P. Edwards The Role of Extranuclear Signaling Actions of Progesterone Receptor in Mediating Progesterone Regulation of Gene Expression and the Cell Cycle Mol. Endocrinol., February 1, 2007; 21(2): 359 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Faivre and C. A. Lange 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 Mol. Cell. Biol., January 15, 2007; 27(2): 466 - 480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Chapman, M. M. Kennelly, K. A. Harper, G. N. Europe-Finner, and S. C. Robson Examining the spatio-temporal expression of mRNA encoding the membrane-bound progesterone receptor-alpha isoform in human cervix and myometrium during pregnancy and labour Mol. Hum. Reprod., January 1, 2006; 12(1): 19 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liang and S. M. Hyder Proliferation of Endothelial and Tumor Epithelial Cells by Progestin-Induced Vascular Endothelial Growth Factor from Human Breast Cancer Cells: Paracrine and Autocrine Effects Endocrinology, August 1, 2005; 146(8): 3632 - 3641. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
