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Regulation and Function of the Cytokine-Inducible SH-2 Domain Proteins, CIS and SOCS3, in Mammary Epithelial Cells

Institut für Medizinische Chemie und Biochemie (S.T.-G., O.G., C.S., W.D.) and Institut für Pathophysiologie (M.T., R.K.), Abteilung Molekulare Pathophysiologie, Universität Innsbruck, and Tyrolean Cancer Research Institute, A-6020 Innsbruck, Austria; Molecular and Cellar Immunology (A.Y.), Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, 812-8582, Japan; Department of Cell and Structural Biology (C.S.), University of Manchester, Manchester M13 9PT, United Kingdom; and Department of Clinical Research (A.Z.), University of Berne, CH-3004 Berne, Switzerland

Address all correspondence and requests for reprints to: Wolfgang Doppler, Institut für Medizinische Chemie und Biochemie, Universität Innsbruck, Fritz Pregl-Strasse 3, A-6020 Innsbruck, Austria. E-mail: Wolfgang.Doppler{at}uibk.ac.at.

The cytokine-inducible src homology 2 (SH-2) proteins, CIS (cytokine inducible SH-2 domain protein) and SOCS3 (suppressor of cytokine signaling 3), are implicated in the negative regulation of prolactin (PRL) receptor-mediated activation of signal transducer and activator of transcription 5 (STAT5). We have studied the expression and function of CIS and SOCS3 proteins in the mouse mammary gland and in HC11 mammary epithelial cells. CIS and SOCS3 were differentially regulated: high expression levels of CIS mRNA were measured during the second half of pregnancy, whereas SOCS3 expression was high during the first 12 d post conceptum. SOCS3 levels increased, whereas CIS levels decreased, in the initial phase of involution. At the beginning of the lactation period both CIS and SOCS3 were high. PRL and epidermal growth factor (EGF) were able to induce CIS and SOCS3, whereas glucocorticoids inhibited their expression in mammary epithelial cells. The effect of EGF was much stronger on SOCS3 than on CIS. Ectopic expression of both SOCS3 and CIS inhibited STAT5 activation. Our data indicate that in the mammary gland CIS and SOCS3 are involved in regulating STAT5 signaling at three different instances: 1) SOCS3 serves as a mediator of the inhibitory EGF effect on PRL-induced STAT5 activation; 2) CIS and SOCS3 play a role as negative feedback inhibitors of PRL action; 3) Inhibition of CIS and SOCS3 expression by glucocorticoids contributes to the positive effect of glucocorticoids on PRL-induced STAT5 activation.

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