Overall, our data are consistent with a hypothetical model in which the juxtaposition of the two ERα, FOXA1, GATA3 binding sites at PRE2 by deletion of approximately 1.4 kb of intervening sequence generates a single extended binding region (Figure 5B) that is causally associated with increased enhancer activity, higher levels of expression of the putative tumor suppressor gene IGFBP5,42 and a reduction in breast cancer risk (OR = 0.77, p = 2.2 × 10−29) that is largely restricted to ER+ disease. Here, ESR1 is linked to breast carcinoma.