Molecular and Cellular Pathobiology Comparison of Increased Aromatase versus ERa in the Generation of Mammary Hyperplasia and Cancer

Factors associated with increased estrogen synthesis increase breast cancer risk. Increased aromatase and estrogen receptor a (ERa) in both normal epithelium and ductal carcinoma in situ lesions are found in conjunction with breast cancer, leading to the idea that altered estrogen signaling pathways predispose the mammary gland to cancer development. Here, we developed a transgenic mouse that conditionally expresses aromatase in the mammary gland, and used it along with a deregulated ERa expression model to investigate the molecular pathways involved in the development of mammary gland preneoplasia and carcinoma. Both increased ERa and aromatase expression led to the development of preneoplasia, but increased preneoplasia, in addition to carcinoma, was found in aromatase overexpressing mice. Increased prevalence of mammary pathologic changes in mice expressing aromatase correlated with increased cyclin E and cyclin-dependent kinase 2 expression. Gain of both ERa and aromatase increased expression of ERa and progesterone receptor, but aromatase produced a higher increase than ERa, accompanied by higher levels of downstream target genes Ccnd1, Myc, and Tnfsf11. In summary, whereas gain of both ERa and aromatase activate abnormal growth pathways in the mammary gland, aromatase induced a wider range of abnormalities that was associated with a higher prevalence of mammary preneoplasia and cancer progression. Cancer Res; 71(16); 5477–87. 2011 AACR.