Regulation of Steroid Hormone Response in Normal and Breast Cancer Cells

................................................................................................................................. 5 LIST OF ORIGINAL COMMUNICATIONS........................................................................... 11 ABBREVIATIONS ..................................................................................................................... 13 INTRODUCTION....................................................................................................................... 15 REVIEW OF THE LITERATURE............................................................................................ 16 1 STEROID HORMONES AND STEROID HORMONE RECEPTORS ............................ 16 1.1 STEROID HORMONES ....................................................................................................................................16 1.2 STEROID HORMONE RECEPTORS....................................................................................................................17 1.2.1 Estrogen receptors ...............................................................................................................................17 1.2.2 Physiological role of ERs in mice ........................................................................................................19 1.2.3 Progesterone receptors.........................................................................................................................20 1.2.4 Physiological role of PR in mice ..........................................................................................................20 1.2.5 Celland tissue-specific expression of PR and ER................................................................................22 1.2.6 Steroid hormone receptors and human diseases ....................................................................................23 2 COREGULATORS .............................................................................................................. 24 2.1 GENERAL STRUCTURE OF COREGULATORS ....................................................................................................24 2.2 COACTIVATORS SRC-1, TIF2/GRIP1 AND AIB1 ..........................................................................................25 2.3 COREPRESSORS N-COR AND SMRT .............................................................................................................26 2.4 COINTEGRATORS CBP, P300 AND PCAF.......................................................................................................27 2.5 HISTONE ACETYLATION (HAT) AND HISTONE DEACETYLATION (HDAC) ACTIVITY OF COREGULATORS ..........28 2.6 CELLAND TISSUE-SPECIFIC EXPRESSION OF COREGULATORS ........................................................................29 2.7 COREGULATOR-RELATED HUMAN DISEASES..................................................................................................30 3 STEROID HORMONE-MEDIATED REGULATION OF TRANSCRIPTION............... 31 3.1 INVOLVEMENT OF CHAPERONE PROTEINS AND DIMERIZATION OF THE RECEPTOR ............................................31 3.2 CONFORMATIONAL CHANGES .......................................................................................................................32 3.3 ESTROGEN AND PROGESTERONE TARGET GENES............................................................................................32 3.4 REGULATION OF CELL CYCLE BY ESTROGEN AND PROGESTERONE ..................................................................34 3.4.1 Cell cycle regulation by estrogen .........................................................................................................35 3.4.2 Cell cycle regulation by progestins.......................................................................................................35 4 CROSSTALK BETWEEN STEROID HORMONE RECEPTOR -MEDIATED SIGNALLING PATHWAY AND OTHER SIGNAL TRANSDUCTION PATHWAYS......... 37 4.1 G PROTEIN-COUPLED RECEPTORS .................................................................................................................37 4.1.1 G protein-coupled receptor 30..............................................................................................................37 4.2 GROWTH FACTORS, KINASE SIGNALLING AND RECEPTOR TRANSACTIVATION..................................................40 4.2.1 ER transactivation ...............................................................................................................................40 4.2.2 PR transactivation ...............................................................................................................................40 5 ANTIHORMONES, RECEPTOR MODULATORS AND AROMATASE INHIBITORS IN BREAST CANCER ............................................................................................................... 41 5.1 ANTIESTROGENS TAMOXIFEN AND TOREMIFENE............................................................................................42 5.2 PURE ANTIESTROGENS ICI 164,384 AND ICI 182,780....................................................................................43 5.3 ANTAGONISM OF ANTIESTROGENS ................................................................................................................43 5.4 AROMATASE INHIBITORS..............................................................................................................................45 6 HORMONE-DEPENDENT BREAST CANCER................................................................ 46 6.1 RISK FACTORS FOR BREAST CANCER .............................................................................................................46