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A Human Breast Cell Model of Preinvasive to Invasive Transition

¹ Life Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, California; ² Department of Pathology and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania; ³ Department of Laboratory Medicine and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; ⁴ Department of Pathology and Laboratory Medicine and Center for Comparative Medicine, University of California, Davis, Davis, California; ⁵ Kansas Masonic Cancer Research Institute, Kansas City, Kansas; ⁶ Department of Pathology, Virginia Commonwealth University, Richmond, Virginia; ⁷ Department of Radiation Oncology, UT Southwestern Medical Center at Dallas, Dallas, Texas; and ⁸ Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

Requests for reprints: Mina J. Bissell or Aylin Rizki, Life Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, One Cyclotron Road, Mailstop 977R225A, Berkeley, CA 94720. Phone: 510-486-4365; Fax: 510-486-5586; E-mail: MJBissell{at}lbl.gov or ARizki{at}vcu.edu.

Key Words: Breast cancer • invasion • basement membrane • metaplasia • matrix metalloproteinase

A crucial step in human breast cancer progression is the acquisition of invasiveness. There is a distinct lack of human cell culture models to study the transition from preinvasive to invasive phenotype as it may occur "spontaneously" in vivo. To delineate molecular alterations important for this transition, we isolated human breast epithelial cell lines that showed partial loss of tissue polarity in three-dimensional reconstituted basement membrane cultures. These cells remained noninvasive; however, unlike their nonmalignant counterparts, they exhibited a high propensity to acquire invasiveness through basement membrane in culture. The genomic aberrations and gene expression profiles of the cells in this model showed a high degree of similarity to primary breast tumor profiles. The xenograft tumors formed by the cell lines in three different microenvironments in nude mice displayed metaplastic phenotypes, including squamous and basal characteristics, with invasive cells exhibiting features of higher-grade tumors. To find functionally significant changes in transition from preinvasive to invasive phenotype, we performed attribute profile clustering analysis on the list of genes differentially expressed between preinvasive and invasive cells. We found integral membrane proteins, transcription factors, kinases, transport molecules, and chemokines to be highly represented. In addition, expression of matrix metalloproteinases MMP9, MMP13, MMP15, and MMP17 was up-regulated in the invasive cells. Using small interfering RNA–based approaches, we found these MMPs to be required for the invasive phenotype. This model provides a new tool for dissection of mechanisms by which preinvasive breast cells could acquire invasiveness in a metaplastic context. [Cancer Res 2008;68(5):1378–87]

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