Exogenous ERα Expression in the Mammary Epithelium Decreases Over Time and Does Not Contribute to p53-Deficient Mammary Tumor Formation in Mice

Lisette M. Cornelissen, Linda Henneman, Anne Paulien Drenth, Eva Schut, Roebi de Bruijn, Sjoerd Klarenbeek, Wilbert Zwart (Corresponding author), Jos Jonkers (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Approximately 75% of all breast cancers express the nuclear hormone receptor estrogen receptor α (ERα). However, the majority of mammary tumors from genetically engineered mouse models (GEMMs) are ERα-negative. To model ERα-positive breast cancer in mice, we exogenously introduced expression of mouse and human ERα in an existing GEMM of p53-deficient breast cancer. After initial ERα expression during mammary gland development, expression was reduced or lost in adult glands and p53-deficient mammary tumors. Chromatin immunoprecipitation (ChIP)-sequencing analysis of primary mouse mammary epithelial cells (MMECs) derived from these models, in which expression of the ERα constructs was induced in vitro, confirmed interaction of ERα with the DNA. In human breast and endometrial cancer, and also in healthy breast tissue, DNA binding of ERα is facilitated by the pioneer factor FOXA1. Surprisingly, the ERα binding sites identified in primary MMECs, but also in mouse mammary gland and uterus, showed an high enrichment of ERE motifs, but were devoid of Forkhead motifs. Furthermore, exogenous introduction of FOXA1 and GATA3 in ERα-expressing MMECs was not sufficient to promote ERα-responsiveness of these cells. Together, this suggests that species-specific differences in pioneer factor usage between mouse and human are dictated by the DNA sequence, resulting in ERα-dependencies in mice that are not FOXA1 driven. These species-specific differences in ERα-biology may limit the utility of mice for in vivo modeling of ERα-positive breast cancer.

Original languageEnglish
Pages (from-to)305-321
Number of pages17
JournalJournal of Mammary Gland Biology and Neoplasia
Volume24
Issue number4
DOIs
Publication statusPublished - 1 Dec 2019

Keywords

  • Breast cancer
  • ERα
  • ERα-cistrome
  • Mouse model
  • Pioneer factor
  • Species-specificity

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