Figure 2

ER-binding and chromatin looping surrounding the AGR2 and AGR3 genes. (a) ER-binding sites surrounding the AGR2 and AGR3 are displayed for ER-positive cell lines and primary tumors. ChIA-Pet data in MCF-7 cells provided by Fullwood and colleagues [23] define an estradiolinduced loop mediated by ER-binding near AGR2 and AGR3 (ER-loop region indicated with red bar). Peaks defined by Welboren and colleagues [34] identify ER-binding upon treatment with estradiol in the proximal promoter of AGR2 and the first intron of AGR3 (MCF-7 minus ligand versus MCF-7 +E2). Treatment with tamoxifen alone (MCF-7 +Tamoxifen) induces ER binding to AGR2 but not AGR3, whereas treatment with fulvestrant alone (MCF-7 +Fulvestrant) induces ER binding to AGR3 but not AGR2. Ross-Innes and colleagues [33] profiled ER binding in tamoxifen-responsive (MCF-7, T47D, ZR75) and tamoxifen-resistant (BT474, TamR) cell lines and ER-positive primary breast tumors (M1-3, metastases; P1-7, poor-outcome tumors; G1-8, good-outcome tumors; ERneg, ER-negative tumor). Using the published peak data, we identified ER binding in only one good-prognosis tumor, whereas poor-prognosis and metastatic primary tumors display increased ER binding. Tamoxifen-resistant and -responsive cell lines display pervasive ER-binding throughout the region. (b) ChIA-PET data from Fullwood and colleagues [23] identify an ER-mediated chromatin loop in MCF-7 cells spanning a 130-kb region that includes the AGR2 and AGR3 genes. The loop region, displayed as a red bar in (a), contains multiple putative ER-binding sites indicated by the location of the bound receptors in the loop. AGR2, anterior gradient 2; E2, estradiol; ER, estrogen receptor; ERE, estrogen response element.