Departments of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia,
Cancer Res. 2011 Aug 15;71(16):5477-87. doi: 10.1158/0008-5472.CAN-10-4652.
Factors associated with increased estrogen synthesis increase breast cancer risk. Increased aromatase and estrogen receptor α (ERα) 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 ERα expression model to investigate the molecular pathways involved in the development of mammary gland preneoplasia and carcinoma. Both increased ERα 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 ERα and aromatase increased expression of ERα and progesterone receptor, but aromatase produced a higher increase than ERα, accompanied by higher levels of downstream target genes Ccnd1, Myc, and Tnfsf11. In summary, whereas gain of both ERα 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.
与雌激素合成增加相关的因素会增加乳腺癌的风险。在乳腺癌中发现正常上皮和导管原位病变中芳香酶和雌激素受体 α(ERα)均增加,这导致改变的雌激素信号通路使乳腺容易发生癌症发展。在这里,我们开发了一种在乳腺中条件性表达芳香酶的转基因小鼠,并使用它与去调节的 ERα 表达模型一起研究参与乳腺前病变和癌发展的分子途径。增加的 ERα 和芳香酶表达均导致前病变的发展,但在过表达芳香酶的小鼠中除了前病变外还发现了癌。表达芳香酶的小鼠中乳腺病理变化的发生率增加与细胞周期蛋白 E 和细胞周期蛋白依赖性激酶 2 表达增加相关。同时增加 ERα 和芳香酶表达增加 ERα 和孕激素受体的表达,但芳香酶的增加高于 ERα,伴随着下游靶基因 Ccnd1、Myc 和 Tnfsf11 的更高水平。总之,虽然 ERα 和芳香酶的增加均激活了乳腺中的异常生长途径,但芳香酶诱导的异常范围更广,与乳腺前病变和癌症进展的更高发生率相关。