title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Park
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Maria
authors.initials: M
authors.lastname: Pallavicini
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Frederick
authors.initials: F
authors.lastname: Baehner
authors.forename: Chong J
authors.initials: CJ
authors.lastname: Park
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019012:Integrin beta1; D016023:Integrins; D000068878:Trastuzumab