Deregulated Estrogen Receptor α and p53 Heterozygosity Collaborate in the Development of Mammary Hyperplasia

Abstract

Both increased estrogen receptor alpha (ER(alpha)) expression and germline disruption of one p53 allele increase breast cancer risk in women. Genetically engineered mouse models of deregulated ER(alpha) expression and p53 haploinsufficiency were used to investigate similarities and differences of each genetic lesion alone and in combination on mammary preneoplasia development. Each genetic lesion independently and in combination led to development of age-dependent preneoplasia, but the highest prevalence was found in compound mice with increased ER(alpha) expression coupled with p53 heterozygosity. All genetic lesions were associated with extracellular signal-regulated kinase 1/2 activation; however, only p53 heterozygous and compound mice showed increased levels of phosphorylated AKT and decreased p27 expression. The highest levels of cell proliferation were found in compound mice, but increased levels were also found with either increased ER(alpha) expression or p53 heterozygosity. Mice with increased ER(alpha) expression showed predicted higher levels of nuclear-localized ER(alpha), but this was attenuated in compound mice in association with a relative increase in Src phosphorylation. Parity protection was limited to p53 heterozygous mice and not found in mice with increased ER(alpha) alone. In summary, increased and deregulated ER(alpha) collaborates with p53 heterozygosity in increasing the risk of mammary preneoplasia development.