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

Background: Upregulation 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. Methods: To 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. Results: Somatic 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. Conclusions: Our results show that synergism between ERβ and p53 inactivation functions to determine important aspects of breast oncogenesis and cancer progression.