Mammary carcinogenesis is preceded by altered epithelial cell turnover in transforming growth factor-alpha and c-myc transgenic mice.

Identification of biomarkers that indicate an increased risk of breast cancer or that can be used as surrogates for evaluating treatment efficacy is paramount to successful disease prevention and intervention. An ideal biomarker would be identifiable before lesion development. To test the hypothesis that changes in cell turnover precede mammary carcinogenesis, we evaluated epithelial cell proliferation and apoptosis in mammary glands from transgenic mice engineered to develop mammary cancer due to expression in mammary epithelia of transforming growth factor alpha (TGF-alpha) or c-myc. In transgenic glands, before lesion development, epithelial cell turnover was enhanced overall compared with nontransgenic glands, indicating that aberrant cell turnover in normal epithelia may contribute to tumorigenesis. In addition, in tumor-containing glands, proliferation in normal epithelia was higher than in tumor-free transgenic glands, suggesting these cell populations influence one another. Finally, although c-myc glands displayed a uniformly high epithelial cell turnover regardless of age, cell turnover was reduced with aging in nontransgenic and TGF-alpha mice, indicating that some growth and death regulatory mechanisms remain intact in TGF-alpha epithelia. These observations support the evaluation of cell turnover as a biomarker of cancer risk and indicator of prevention/treatment efficacy in preclinical models and warrant validation in human breast cancer.