Figure 5.

Changes in key DREAM mediators and hypothetical model. (A) p53 protein expression in the surgical specimens of responders and non-responders is similar (p = ns, t-test). p53 protein was detected immunohistochemically using the DO-7 antibody. Expression was calibrated using image analysis and then scored manually using a histoscore calculation (see ref. [42]). (B) Log2 fold change (surgical over core samples) in responders or non-responders for TP53 (p53), CDKN1A (p21), FOXM1 and MYBL2, after estradiol. ∗∗P < 0.01, ns – not significant. (C) In this hypothetical model, estrogen therapy is associated with increases in p21 and decreases in FOXM1 and/or MYBL2. The mechanism for these changes in responding patients is currently unknown and this is indicated by dashed lines. Increases in p21 (or cyclin dependent kinase inhibitors, not shown) will lead to hypophosphorylated forms of the retinoblastoma family proteins (RB, p107/RBL1 and p130/RBL2). Hypophosphorylated p130 binds with the LIN52 member of MuvB core proteins resulting in a stable DREAM repressor complex which binds to the CHR element of cell cycle genes through another MuvB core protein (LIN54). The DREAM complex suppresses cell cycle genes causing reversible cell cycle arrest (quiescence). The DREAM complex can be destabilized by increases in pro-proliferative MuvB co-factors, FOXM1 and MYBL2. When MuvB is complexed with these proteins and bound to the CHR motif of the same cell cycle genes, it activates transcription resulting in proliferation.