Mammary ductal dysplasia is a phenotype observed in precancerous lesions and early-stage breast cancer. However, the mechanism of dysplasia formation remains elusive. Here we show, by establishing a novel dysplasia model system, that estrogen, a female hormone, has the potential to cause mammary ductal dysplasia. We injected estradiol (E2), the most active form of estrogen, daily into scid mice with a defect in non-homologous end joining repair and observed dysplasia formation with cell proliferation at day 30. The protooncogene Myc is a downstream target of estrogen signaling, and we found that its expression is augmented in mammary epithelial cells in this dysplasia model. Treatment with a Myc inhibitor reduced E2-induced dysplasia formation. Moreover, we found that isoflavones inhibited E2-induced dysplasia formation. Our dysplasia model system provides insights into the mechanistic understanding of breast tumorigenesis and the development of breast cancer prevention.

乳腺导管发育不良是在癌前病变和早期乳腺癌中观察到的表型。但是，发育异常形成的机制仍然难以捉摸。在这里，我们通过建立新型的异型增生模型系统来表明，雌激素（一种女性激素）具有引起乳腺导管异型增生的潜力。我们每天向具有非同源末端连接修复缺陷的scid小鼠注射雌二醇（E2），这是最活跃的雌激素形式，并在第30天观察到异型增生形成并伴随细胞增殖。原癌基因Myc雌激素信号传导的下游靶点，是我们发现，在这种发育异常模型中，其表达在乳腺上皮细胞中增加。用Myc抑制剂治疗可减少E2诱导的发育异常。此外，我们发现异黄酮抑制E2诱导的异型形成。我们的发育异常模型系统提供了对乳腺肿瘤发生的机理理解和预防乳腺癌发展的见识。