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| The EMBO Journal
(1998) 17, 2008–2018, doi:10.1093/emboj/17.7.2008 |
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| Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor |
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| Antimo Migliaccio1, Domenico Piccolo1, Gabriella Castoria1, Marina Di Domenico1, Antonio Bilancio1, Maria Lombardi1, Wenrong Gong2, Miguel Beato2 and Ferdinando Auricchio1 |
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1 Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, II Università di Napoli, Largo S.Aniello a Caponapoli, 2, 80138 Napoli, Italy 2 Institut für Molekularbiologie und Tumorforschung, Philipps-Universität Marburg, Emil-Mannkopff-Strasse 2, D-35037 Marburg, Germany To whom correspondence should be addressed Ferdinando Auricchio, ferauric@cds.unina.it Received 16 October 1997; Revised 26 January 1998; Accepted 9 February 1998. |
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| Abstract |
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| The molecular mechanisms by which ovarian hormones stimulate growth of breast tumors are unclear. It has been reported previously that estrogens activate the signal-transducing Src/p21ras/Erk pathway in human breast cancer cells via an interaction of estrogen receptor (ER) with c-Src. We now show that progestins stimulate human breast cancer T47D cell proliferation and induce a similar rapid and transient activation of the pathway which, surprisingly, is blocked not only by anti-progestins but also by anti-estrogens. In Cos-7 cells transfected with the B isoform of progesterone receptor (PRB), progestin activation of the MAP kinase pathway depends on co-transfection of ER. A transcriptionally inactive PRB mutant also activates the signaling pathway, demonstrating that this activity is independent of transcriptional effects. PRB does not interact with c-Src but associates via the N-terminal 168 amino acids with ER. This association is required for the signaling pathway activation by progestins. We propose that ER transmits to the Src/p21ras/Erk pathway signals received from the agonist-activated PRB. These findings reveal a hitherto unrecognized cross-talk between ovarian hormones which could be crucial for their growth-promoting effects on cancer cells. |
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| Keywords: estradiol receptor, progesterone receptor, progestins, proliferation, signal transduction |
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