The glucocorticoid receptor signalling in breast cancer

Abstract

Glucocorticoids are provided as co-medication with chemotherapy in breast cancer, albeit several lines of evidence indicate that their use may have diverse effects and in fact may inhibit chemosensitivity. The molecular basis of glucocorticoid-induced resistance to chemotherapy in breast cancer remains poorly defined. Recent researchers, in an attempt to clarify some aspects of the underlying pathways, provide convincing evidence that glucocorticoids induce effects that are dependent upon the glucocorticoid receptor -mediated transcriptional regulation of specific genes known to play key roles in cellular/tissue functions, including growth, apoptosis, differentiation, metastasis and cell survival. In this review, we focus on how glucocorticoid-induced chemoresistance in breast cancer is mediated by the glucocorticoid receptor, unraveling the molecular interplay of glucocorticoid receptor signaling with other signaling cascades prevalent in breast cancer. We also include a detailed description of glucocorticoid receptor structure and function, summarizing data gained during recent years into the mechanism(s) of the cross-talk between the glucocorticoid receptor and other signaling cascades and secondary messengers, via which glucocorticoids exert their pleiotropic effects.

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Genomic and complementary DNA, protein structures and functional domains of human GR isoforms. The human GR gene consists of 10 exons. Exon 1 is an untranslated region; exon 2 encodes the N-terminal ‘immunogenic’ domain; exons 3 and 4 encode the DNA-binding domain;and exons 5 through 9 encode the hinge region and the LBD. The GR gene contains two terminal exon 9s (9α and 9β), which are alternatively spliced to produce the classic GR-α (GRα-A) and the non-ligand-binding GRβ-A, which exerts dominant negative effects upon GR-α (GRα-A). C-terminal domains colored as light green and yellow in GRαs and GR-βs show unique portions of their amino acid sequences. GR-α N-terminal translational isoforms expressed from a single GR-α transcript are shown in the middle of the figure. The GR-β transcript may also produce similar N-terminal isoforms from the same start sites as GR-α. AF-1 and -2, activation function 1 and 2; DBD, DNA-binding domain; HR, hinge region; LBD, ligand-binding domain; NL1 and 2, nuclear translocation signal 1 and 2. ‘From G. P. Chrousos, T. Kino. Intracellular glucocorticoid signalling: A formerly simple system turns stochastic. Sci. STKE 2005, pe48. Reprinted with permission from AAAS’.

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Shuttling of GR-α between the cytoplasm and the nucleus and its transactivating or transrepressive activities. Possible sites of intervention, which may change the activity of GR-α are indicated by numbers. GR: glucocorticoid receptor; GREs: glucocorticoid-responsive elements; TFREs: transcription factor responsive elements; HSP: heat shock proteins; TF: transcription factor. ‘This article (figure) was published in Journal of Steroid Biochem. Mol. Biol. 85, T. Kino, MU De Martino, E. Charmandari, M. Mirani, GP. Chrousos, Tissue glucocorticoid resistance/hypersensitivity syndromes, 457–467, Copyright Elsevier 2003’.