β1 Integrin Inhibitory Antibody Induces Apoptosis of Breast Cancer Cells, Inhibits Growth, and Distinguishes Malignant from Normal Phenotype in Three Dimensional Cultures and In vivo
- 1 February 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 66 (3), 1526-1535
- https://doi.org/10.1158/0008-5472.can-05-3071
Abstract
Current therapeutic approaches to cancer are designed to target molecules that contribute to malignant behavior but leave normal tissues intact. β1 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 β1 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 β1 integrin signaling, resulting in malignant reversion. To investigate β1 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 β1 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 β1 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 β1 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)Keywords
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This publication has 52 references indexed in Scilit:
- Targeted disruption of β1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor inductionCancer Cell, 2004
- Integrin expression and survival in human breast cancerEuropean Journal of Surgical Oncology, 2004
- Ionizing radiation induces up-regulation of functional β 1-integrin in human lung tumour cell lines in vitroInternational Journal of Radiation Biology, 2002
- Mechanism of action of trastuzumab and scientific updateSeminars in Oncology, 2001
- Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cellsOncogene, 2001
- Analysis of cadherin/catenin complexes in transformed thyroid epithelial cells: Modulation by beta 1 integrin subunitEuropean Journal of Cell Biology, 2000
- Integrin expression in breast cancer cytology: a novel predictor ofaxillary metastasisEuropean Journal of Surgical Oncology, 1996
- Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression.The Journal of cell biology, 1989
- Purification and characterization of mammalian integrins expressed by a rat neuronal cell line (PC12): evidence that they function as alpha/beta heterodimeric receptors for laminin and type IV collagen.The Journal of cell biology, 1988
- A new diploid nontumorigenic human breast epithelial cell line isolated and propagated in chemically defined mediumIn Vitro Cellular & Developmental Biology, 1987