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Amphiregulin deletion strongly attenuates the development of estrogen receptor-positive tumors in p53 mutant mice

Abstract

Purpose

The epidermal growth factor receptor ligand, Amphiregulin, is a transcriptional target of estrogen receptor alpha and is required for pubertal mammary gland development. Previous studies using immortalized human breast cancer cell line xenografts have suggested that Amphiregulin may be an important effector of estrogen receptor alpha during breast cancer development, at least in immune-compromised animals. Here, we evaluate the requirement for Amphiregulin in an immune-competent mouse model which is prone to developing estrogen receptor-positive tumors.

Methods

We have intercrossed mice with mammary-specific mutation of p53 with mice deficient in Amphiregulin in order to assess the requirement for Amphiregulin in the initiation and progression of both estrogen receptor-positive and estrogen receptor-negative mammary tumors.

Results

Deletion of Amphiregulin significantly delayed the onset of palpable mammary tumors and also strongly reduced the proportion of estrogen receptor alpha-positive tumors formed. Upon necropsy, no substantial differences in the prevalence of non-palpable lesions were observed between cohorts, suggesting that the importance of Amphiregulin in mammary tumorigenesis is limited to the post-initiation phase.

Conclusions

This study underlines the importance of the EGFR ligand, Amphiregulin, as a key mediator of estrogen receptor action in breast cancer.

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Author information

Correspondence to Paraic A. Kenny.

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Each author declares that he/she has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal experiments were approved by the Institutional Animal Care and Utilization Committee of the University of Wisconsin—La Crosse (Approval #15-15). This article does not contain any studies with human participants performed by any of the authors.

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Supplementary Figure 1: Substantial rescue of mammary outgrowth defect in Areg-/- glands by transgenic expression of Trp53R172H. (A) Representative images of inguinal mammary glands from either Areg-/-;Tp53+/+;MMTV-Cre (left) and Areg-/-;Trp53+/R172H;MMTV-Cre (right) mice at various ages showing increased ductal development in glands expressing mutant Trp53. The regional extent of ductal elongation is marked with a dashed line in each case. (B) Quantification of mammary ductal area in Areg-/- mice with wild-type (n = 10) and mutant (n = 10) Trp53. (C) Representative PCNA immunostaining of 3 mice of each genotype (all estrus matched) showing higher proportions of luminal cells positive for this proliferation marker in the mice carrying the Trp53R172H allele (TIF 6213 kb)

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Meier, D.R., Girtman, M.A., Lofgren, K.A. et al. Amphiregulin deletion strongly attenuates the development of estrogen receptor-positive tumors in p53 mutant mice. Breast Cancer Res Treat (2019). https://doi.org/10.1007/s10549-019-05507-2

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Keywords

  • Amphiregulin
  • Epidermal growth factor receptor
  • Breast cancer
  • Genetically engineered mouse model