Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis

Abstract

BackgroundUpregulation of estrogen receptor beta (ERβ) in breast cancer cells is associated with epithelial maintenance, decreased proliferation and invasion, and a reduction in the expression of the receptor has been observed in invasive breast tumors. However, proof of an association between loss of ERβ and breast carcinogenesis is still missing.MethodsTo study the role of ERβ in breast oncogenesis, we generated mouse conditional mutants with specific inactivation of ERβ and p53 in the mammary gland epithelium. For epithelium-specific knockout of ERβ and p53, ERβ F/F and p53 F/F mice were crossed to transgenic mice that express the Cre recombinase under the control of the human keratin 14 promoter.ResultsSomatic loss of ERβ significantly accelerated formation of p53-deficient mammary tumors. Loss of the receptor also resulted in the development of less differentiated carcinomas with stronger spindle cell morphology and decreased expression of luminal epithelial markers.ConclusionsOur results show that synergism between ERβ and p53 inactivation functions to determine important aspects of breast oncogenesis and cancer progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0872-z) contains supplementary material, which is available to authorized users.

Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis

“… 99 , 100 In a conditional p53 knockout mouse model, the formation of mammary tumors was sped up by the simultaneous knockout of Esr2 (mouse gene coding ERβ). 101 Tumors in the double knockout mice also displayed more malignant phenotypes, suggesting ERβ execute its tumor-suppressing role at least partly by interacting with p53. ERβ signaling in breast cancer and other circumstances are not as well elucidated as ERα at the moment.…”

“…ERβ signaling in breast cancer and other circumstances are not as well elucidated as ERα at the moment. 101 However, since more studies are implying a significant position for ERβ in the mammary tumorigenesis, it will not be surprising if ERβ turn out to be just as crucial as ERα, if not more. 80 …”

Quantitative mapping of RNA-mediated nuclear estrogen receptor β interactome in human breast cancer cells

“…Indeed, ERβ inhibits BC cells proliferation and invasion, both with and without ligand 3–5 , showing an additive effect with antiestrogen 6 , 7 . Furthermore, loss of ERβ expression in invasive BC, in early stages of ductal tumors 8 , 9 and in breast tumorigenesis have been reported 10 , together with a positive prognostic value of the presence of ERβ in cancer cells 11 that may also be an indicator of their responsiveness to endocrine therapy 12 , 13 . Although some of the results obtained in clinical samples have been challenged, due to the existence of multiple isoform of this protein and uncertainties concerning the specificity of the available antibodies for its detection in tissue specimens, all these evidences points to a key role of ERβ in BC biology.…”

ERβ alters the chemosensitivity of luminal breast cancer cells by regulating p53 function

“…ERα was indeed found to bind to and repress p53-depedent transcription and its associated tumor suppressor function [ 32 – 34 ] and disruption of this interaction by radiation restores p53 function [ 35 , 36 ]. In contrast to ERα and similar to p53 downregulation, ERβ expression decreases in breast cancer [ 37 , 38 ]. The reduced levels of the two proteins in human tumors may explain the observed collaboration of ERβ and p53 inactivation in mouse breast tumor development [ 37 ].…”