Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo.
Current therapeutic approaches to cancer are designed to target molecules that contribute to malignant behavior but leave normal tissues intact. beta(1) 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 beta(1) 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 beta(1) integrin signaling, resulting in malignant reversion. To investigate beta(1) 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 beta(1) 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 beta(1) 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 beta(1) 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.
Park
Catherine C
CC
Departments of Radiation Oncology and Pathology, University of California-San Francisco/Mt. Zion Cancer Center, 1600 Divisadero Street, San Francisco, CA 94143-1708, USA. park@radonc17.ucsf.edu
Zhang
Hui
H
Pallavicini
Maria
M
Gray
Joe W
JW
Baehner
Frederick
F
Park
Chong J
CJ
Bissell
Mina J
MJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D016023:Integrins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019012:Integrin beta1; D016023:Integrins; D000068878:Trastuzumab