Transforming growth factor alpha- and c-myc-induced mammary carcinogenesisin transgenic mice

The growth factor transforming growth factor alpha (TGF alpha) and the nucl ear transcription factor c-myc often are overexpressed by human breast cant er cells. To produce models of breast disease with these etiologies, mice w ere generated that carried TGF-alpha- or c-myc-encoding transgenes. Transge ne targeting employed the whey acidic protein (WAP) gene promoter, which is expressed in pregnant and lactating mammary epithelial cells. Non-virgin W AP-TGF alpha transgenic mice displayed accelerated mammary development duri ng pregnancy, delayed post-parturient mammary involution, a progressive inc rease in the number of hyperplastic alveolar nodules (HANs), and developmen t of mammary carcinoma with a mean latency of 9 months. Non-virgin WAP-c-my c transgenic mice displayed accelerated mammary gland development during pr egnancy and development of mammary carcinomas with a latency of 8 months, B itransgenic mice carrying both WAP-TGF alpha and WAP-c-myc displayed a dram atic acceleration of tumor development. These models identify the overexpre ssion of TGF alpha or c-myc as etiological factors in the development of ma mmary neoplasia and demonstrate the increased severity of disease when both molecular alterations are present in the same cell.