Published online before print May 24, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061010

Accepted for publication March 20, 2007.

Article

Alterations of Gene Expression in the Development of Early Hyperplastic Precursors of Breast Cancer

Sangjun Lee^*, Dan Medina, Anna Tsimelzon, Syed K. Mohsin, Sufeng Mao, Yun Wu, and D. Craig Allred^*@

From the Department of Pathology,* Washington University School of Medicine, St. Louis, Missouri; the Department of Molecular and Cellular Biology and the Breast Center, Baylor College of Medicine, Houston, Texas; and the Department of Pathology, Riverside Methodist Hospital, Columbus, Ohio

^@ To whom correspondence should be addressed. E-mail: dcallred{at}path.wustl.edu.

	Abstract

Enlargement of normal terminal duct lobular units (TDLUs) by hyperplastic columnar epithelial cells is one of the most common abnormalities of growth in the adult female human breast. These hyperplastic enlarged lobular units (HELUs) are important clinically as the earliest histologically identifiable potential precursor of breast cancer. The causes of the hyperplasia are unknown but may include estrogen-simulated growth mediated by estrogen receptor-, which is highly elevated in HELUs and may be fundamental to their development. The present study used DNA microarray technology and RNA from microdissected pure epithelial cells to examine changes in gene expression and molecular pathways associated with the development of HELUs from TDLUs. The results suggest that HELUs evolve from TDLUs primarily by reactivation of pathways involved in embryonic development and suppression of terminal differentiation. Changes in ERBB genes were particularly prominent, including a uniform switch in ligands for the ERBB1 receptor (14-fold decrease in epidermal growth factor and 10-fold increase in amphiregulin, respectively) in HELUs compared with TDLUs. Epidermal growth factor regulates terminal differentiation in adult breast and amphiregulin is critical to normal embryonic breast development. Because HELUs are such early potential precursors of breast cancer, targeting some of these alterations may be especially promising strategies for breast cancer prevention.