| First Author | Warner M | Year | 2020 |
| Journal | Proc Natl Acad Sci U S A | Volume | 117 |
| Issue | 9 | Pages | 4902-4909 |
| PubMed ID | 32075916 | Mgi Jnum | J:285743 |
| Mgi Id | MGI:6394035 | Doi | 10.1073/pnas.1920478117 |
| Citation | Warner M, et al. (2020) Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERbeta gene. Proc Natl Acad Sci U S A 117(9):4902-4909 |
| abstractText | Disagreements about the phenotype of estrogen receptor beta (ERbeta) knockout mouse, created by removing the DNA-binding domain of the ERbeta gene or interruption of the gene with a neocassette (Oliver Smithies ERbeta knockout mice [ERbeta(OS-/-)]), prompted us to create an ERbeta knockout mouse by deleting the ERbeta gene with the use of CRISPR/Cas9 technology. We confirmed that the ERbeta gene was eliminated from the mouse genome and that no ERbeta mRNA or protein was detectable in tissues of this mouse. Overall the phenotype of the ventral prostate (VP) and mammary gland (MG) in ERbeta(crispr-/-) mice was similar to, but more severe than, that in the ERbeta(OS-/-)mice. In the VP of 6-mo-old ERbeta(crispr-/-) mice there was epithelial hyperplasia, fibroplasia, inflammation, stromal overgrowth, and intraductal cancer-like lesions. This was accompanied by an increase in Ki67 and P63 and loss in DACH1 and PURalpha, two androgen receptor (AR) repressors. In the MG there was overexpression of estrogen receptor alpha and progesterone receptor, loss of collagen, increase in proliferation and expression of metalloproteases, and invasive epithelium. Surprisingly, by 18 mo of age, the number of hyperplastic foci was reduced, the ducts of the VP and MG became atrophic, and, in the VP, there was massive immune infiltration and massive desquamation of the luminal epithelial cells. These changes were coincident with reduced levels of androgens in males and estrogens in females. We conclude that ERbeta is a tumor suppressor gene in the VP and MG where its loss increases the activity AR and ERalpha, respectively. |
