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

Teresa A. Rose-Hellekant, Kristin M. Wentworth, Sarah Nikolai, Donald W. Kundel, Eric P. Sandgren

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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 α (TGF-α) 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-α mice, indicating that some growth and death regulatory mechanisms remain intact in TGF-α 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.

Original languageEnglish (US)
Pages (from-to)1821-1832
Number of pages12
JournalAmerican Journal of Pathology
Volume169
Issue number5
DOIs
StatePublished - Nov 2006
Externally publishedYes

Bibliographical note

Funding Information:
Supported in part by the National Institutes of Health (grants K01-RR00145 to T.A.R.-H., R01-CA64843 to E.P.S., and ES09090 ). Regular Articles

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