No abstract

Stress enhances glucocorticoid (GC) synthesis, which alters inflammation and immune responses, as well as cellular proliferation and apoptosis in a number of tissues. Increasingly, stress has been associated with cancer progression, and in particular in breast cancer. Consequently, an operational glucocorticoid receptor system in breast tissue influences breast cancer development. In this review, we summarize the data on the GC/GR system in normal and tumoral breast tissue. We also review the molecular mechanisms by which GCs control apoptosis and proliferation in breast cancer models and how GCs alter the chemotherapy of breast cancer treatment when used in combination. Finally, we discuss the participation of GR in breast tumorigenesis under hormone replacement therapy.

(18-20, 50, 53, 59). The mitochondrial adapter MAVS/ IPS-1/Cardif/VISA is directly downstream of the helicases and acts as a pivotal point in the cascade leading to activation of the transcription factors IRF-3 and -7 and NF-B, which synergistically regulate IFN-␤ gene expression (21,30,45,49,58). Secreted IFN-␣/␤ binds to its cognate IFNAR receptor in neighboring cells and initiates a second wave of IFN response, mediated by a complex known as ISGF3, which is composed of STAT-1, STAT-2, and IRF-9 transcription factors (27,39,54). During the second wave, IFN production is amplified with the expression of multiple IFN-␣ subtypes and hundreds of interferon-stimulated genes (ISGs), including recently identified IB kinase ε (IKKε)-specific genes such as ADAR-1, IFIT3, and OAS1 (51).The MAVS adapter contains an amino-terminal caspase activation and recruitment domain (CARD) that interacts with the CARDs of RIG-I/Mda5 and a carboxy-terminal transmembrane (TM) domain that anchors MAVS to the outer mitochondrial membrane (21,30,45,58). The essential role of MAVS in antiviral signaling was demonstrated by the failure of MAVS-deficient mice to mount a proper IFN response to poly(I ⅐ C) stimulation and by their severely compromised immune defense against virus infection (24, 49). Interestingly, MAVS expression alone, in the absence of virus infection, is sufficient to trigger the IRF and NF-B pathways leading to IFN production. Engagement of MAVS by active RIG-I/Mda5 leads to dimerization (3) and formation of a mitochondrial platform where multiple signaling molecules converge to mediate activation of the classical IKK complex and/or the IKK-related kinases 21,30,31,42,43,45,58,60,61).TBK-1 and IKKε activate the IRF pathway by direct phosphorylation of IRF-3 and IRF-7 in their C-terminal regulatory region (9,26,29,34,46,52). Analysis of knockout mice demonstrated that the ubiquitously expressed TBK-1 is the major mediator of IRF-3/-7 phosphorylation and initiator of the antiviral response (15,35,38). Disruption of IKKε expression on the other hand had a minimal effect on the activation of IRF-3/-7 and was considered dispensable for the induction of the IFN response (15,35,38). However, following viral infection IKKε, but not TBK-1, phosphorylates STAT-1 on serine 708 and increases expression of genes such as ADAR-1, IFIT3, and OAS1 (51). Importantly, this observation suggests that differences at the level of substrate specificity may exist for the two kinases (28, 51). Mechanistic differences in the activation of TBK-1 and IKKε may also be expected, based on differences in cytoplasmic localization of the two kinases as well as the observation that IKKε is directly recruited to the mitochondrial network via MAVS following virus infection, whereas TBK-1 remains largely cytoplasmic (16, 23, 25, 30).