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ß₁ Integrin Inhibitory Antibody Induces Apoptosis of Breast Cancer Cells, Inhibits Growth, and Distinguishes Malignant from Normal Phenotype in Three Dimensional Cultures and In vivo

Departments of ¹ Radiation Oncology and ² Pathology, University of California, San Francisco, California; ³ Life Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, California; ⁴ School of Natural Sciences, University of California, Merced, California; and ⁵ Department of Mathematics and Statistics, San Diego State University, San Diego, California

Requests for reprints: Catherine Park, University of California in San Francisco/Mt. Zion Cancer Center, 1600 Divisadero Street H1031, San Francisco, CA 94143-1708. Phone: 415-353-7186; Fax: 415-353-9883; E-mail: park{at}radonc17.ucsf.edu.

Current therapeutic approaches to cancer are designed to target molecules that contribute to malignant behavior but leave normal tissues intact. ß₁ integrin is a candidate target well known for mediating cell-extracellular matrix (ECM) interactions that influence diverse cellular functions; its aberrant expression has been implicated in breast cancer progression and resistance to cytotoxic therapy. The addition of ß₁ integrin inhibitory agents to breast cancer cells at a single-cell stage in a laminin-rich ECM (three-dimensional lrECM) culture was shown to down-modulate ß₁ integrin signaling, resulting in malignant reversion. To investigate ß₁ integrin as a therapeutic target, we modified the three-dimensional lrECM protocol to approximate the clinical situation: before treatment, we allowed nonmalignant cells to form organized acinar structures and malignant cells to form tumor-like colonies. We then tested the ability of ß₁ integrin inhibitory antibody, AIIB2, to inhibit tumor cell growth in several breast cancer cell lines (T4-2, MDA-MB-231, BT474, SKBR3, and MCF-7) and one nonmalignant cell line (S-1). We show that ß₁ integrin inhibition resulted in a significant loss of cancer cells, associated with a decrease in proliferation and increase in apoptosis, and a global change in the composition of residual colonies. In contrast, nonmalignant cells that formed tissue-like structures remained resistant. Moreover, these cancer cell–specific antiproliferative and proapoptotic effects were confirmed in vivo with no discernible toxicity to animals. Our findings indicate that ß₁ integrin is a promising therapeutic target, and that the three-dimensional lrECM culture assay can be used to effectively distinguish malignant and normal tissue response to therapy. (Cancer Res 2006; 66(3): 1526-35)

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