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Interactions between progesterone receptor (PR) and signal transducer and activator of transcription 3 (Stat3)-mediated signaling pathways have already been described. In the present study, we explored the capacity of Stat3 to functionally interact with progesterone receptor (PR) and modulate PR transcriptional activation in breast cancer cells. We found that the synthetic progestin medroxyprogesterone acetate (MPA) induced the association of a PR/Stat3 complex in which Stat3 acts as a coactivator of PR. We demonstrated that Stat3 activation is required for MPA modulation of the endogenous genes bcl-X and p21(CIP1) which are involved in MPA-induced cell cycle regulation. Stat3 activity as a coactivator of PR was observed in both the classical and nonclassical ligand activated-PR transcriptional mechanisms, since the effects described were identified in the bcl-X promoter which contains a progesterone responsive element and in the p21(CIP1) promoter which carries Sp1 binding sites where PR is recruited via the transcription factor Sp1. The data herein presented identifies a potential therapeutic intervention for PR-positive breast tumors consisting of targeting Stat3 function or PR/Stat3 interaction which will result in the inhibition of PR function.

Tumor necrosis factor alpha (TNF alpha) enhances proliferation of chemically-induced mammary tumors and of T47D human cell line through not fully understood pathways. Here, we explored the intracellular signaling pathways triggered by TNF alpha, the participation of TNF alpha receptor (TNFR) 1 and TNFR2 and the molecular mechanism leading to breast cancer growth. We demonstrate that TNFalpha induced proliferation of C4HD murine mammary tumor cells and of T47D cells through the activation of p42/p44 MAPK, JNK, PI3-K/Akt pathways and nuclear factor-kappa B (NF-kappa B) transcriptional activation. A TNF alpha-specific mutein selectively binding to TNFR1 induced p42/p44 MAPK, JNK, Akt activation, NF-kappa B transcriptional activation and cell proliferation, just like wild-type TNF alpha, while a mutein selective for TNFR2 induced only p42/p44 MAPK activation. Interestingly, blockage of TNFR1 or TNFR2 with specific antibodies was enough to impair TNF alpha signaling and biological effect. Moreover, in vivo TNF alpha administration supported C4HD tumor growth. We also demonstrated, for the first time, that injection of a selective inhibitor of NF-kappa B activity, Bay 11-7082, resulted in regression of TNF alpha-promoted tumor. Bay 11-7082 blocked TNF alpha capacity to induce cell proliferation and up-regulation of cyclin D1 and of Bcl-xLin vivo and in vitro. Our results reveal evidence for TNF alpha as a breast tumor promoter, and provide novel data for a future therapeutic approach using TNF alpha antagonists and NF-kappa B pharmacological inhibitors in established breast cancer treatment.

Although it is known that IGF-1 increases T lymphocyte proliferation, the regulation of its receptor expression during the process has not been defined. Consequently the regulation of IGF-1R expression by IGF-1 and the activation events in human blood T lymphocytes and the Jurkat T cell line were now investigated. IGF-1R expression in nonstimulated Jurkat cells was confirmed and downregulation by IGF-1 was demonstrated. In addition, both cell types showed a time-dependent reduction in the number of IGF-1R-positive cells following activation, which was increased by IGF-1. In Jurkat cells the negative regulation of IGF-1R levels was correlated with the appearance and continuous increase in IL-2R. In T lymphocytes the decrease in IGF-1R expression was faster, reaching its plateau after 3 h of activation. Our findings suggest that loss of the IGF-1R is one of the initial events of the activation process not regulated by IL-2.

Receptors for insulin and insulin-like growth factor-1 (IGF-1) have been demonstrated on activated T-lymphocytes. The question is whether receptors for insulin or IGF-1 have any function in these cells. In this study we demonstrate that the concentration of IGF-1 in commercial samples of fetal calf serum is about 70 times that of insuli. Moreover, antibodies of IGF-1 reduce responses of human peripheral blood mononuclear cells to PHA by about 50% whereas antibodies to insulin have no demonstrable effect. These observations suggest that binding of IGF-1 to specific receptors contributes to the proliferative responses of activated T-lymphocytes.