ERa over-expression does not accelerate development of p53-deficient mammary tumors in mice [ChIP-Seq]

About 75% of all breast cancers express the nuclear hormone receptor oestrogen receptor a (ERa). However, the majority of mammary tumors from genetically engineered mouse models are ERa-negative. To model ERa-positive breast cancer in mice, we exogenously introduced expression of mouse and human ERa in an existing p53-deficiency driven breast cancer mouse model. After initial ERa expression during development of the mammary gland, expression was reduced or lost in adult glands and p53-deficient mammary tumors. ChIP-sequencing analysis of primary mouse mammary epithelial cells (MMECs) derived from these models, in which expression of the ERa constructs was induced in vitro, confirmed interaction of ERa with the DNA. In human breast and endometrial cancer, the pioneer factor FOXA1 is known to be essential to facilitate ERa/DNA binding. Surprisingly, the ERa binding sites identified in primary MMECs, but also in mouse mammary gland and uterus, showed a high enrichment of ERE motifs, but were devoid of Forkhead motifs. Furthermore, exogenous introduction of FOXA1 and GATA3 in ERa-expressing MMECs was not sufficient to promote ERa-responsiveness of these cells. Together, this suggests that species-specific differences in ERa-cistromes between mouse and human are dictated by the DNA sequence, resulting in ERa-dependencies in mice that are not FOXA1 driven and potentially not tumorigenic. These species-specific differences in ERa-biology can limit the use of mouse models in ERa-positive breast cancer research. Overall design: Binding of ERa in MCF7 cells and HA-tagged human ERa or HA-tagged mouse ERa in primary MMECs profiled by ChIP-seq (Chromatin Immunoprecipitation followed by deep sequencing).