Pluto Bioinformatics

GSE127862: ER over-expression does not accelerate development of p53-deficient mammary tumors in mice [RNA-Seq]

Bulk RNA sequencing

About 75% of all breast cancers express the nuclear hormone receptor oestrogen receptor (ER). However, the majority of mammary tumors from genetically engineered mouse models are ER-negative. To model ER-positive breast cancer in mice, we exogenously introduced expression of mouse and human ER in an existing p53-deficiency driven breast cancer mouse model. After initial ER 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 ER constructs was induced in vitro, confirmed interaction of ER with the DNA. In human breast and endometrial cancer, the pioneer factor FOXA1 is known to be essential to facilitate ER/DNA binding. Surprisingly, the ER 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 ER-expressing MMECs was not sufficient to promote ER-responsiveness of these cells. Together, this suggests that species-specific differences in ER-cistromes between mouse and human are dictated by the DNA sequence, resulting in ER-dependencies in mice that are not FOXA1 driven and potentially not tumorigenic. These species-specific differences in ER-biology can limit the use of mouse models in ER-positive breast cancer research. SOURCE: Lisette Cornelissen (l.cornelissen@nki.nl) - The Netherlands Cancer Institute