A human breast cell model of preinvasive to invasive transition

Aylin Rizki, Valerie M. Weaver, Sun Young Lee, Gabriela I. Rozenberg, Koei Chin, Connie A. Myers, Jamie L. Bascom, Joni D. Mott, Jeremy R. Semeiks, Leslie R. Grate, I. Saira Mian, Alexander D Borowsky, Roy A. Jensen, Michael O. Idowu, Fanqing Chen, David J. Chen, Ole W. Petersen, Joe W. Gray, Mina J. Bissell

Research output: Contribution to journalArticle

106 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1378-1387
Number of pages10
JournalCancer Research
Volume68
Issue number5
DOIs
StatePublished - Mar 1 2008

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Rizki, A., Weaver, V. M., Lee, S. Y., Rozenberg, G. I., Chin, K., Myers, C. A., Bascom, J. L., Mott, J. D., Semeiks, J. R., Grate, L. R., Mian, I. S., Borowsky, A. D., Jensen, R. A., Idowu, M. O., Chen, F., Chen, D. J., Petersen, O. W., Gray, J. W., & Bissell, M. J. (2008). A human breast cell model of preinvasive to invasive transition. Cancer Research, 68(5), 1378-1387. https://doi.org/10.1158/0008-5472.CAN-07-2225