title: Imaging the urokinase plasminongen activator receptor in preclinical breast cancer models of acquired drug resistance.
abstract: Subtype-targeted therapies can have a dramatic impact on improving the quality and quantity of life for women suffering from breast cancer. Despite an initial therapeutic response, cancer recurrence and acquired drug-resistance are commonplace. Non-invasive imaging probes that identify drug-resistant lesions are urgently needed to aid in the development of novel drugs and the effective utilization of established therapies for breast cancer. The protease receptor urokinase plasminogen activator receptor (uPAR) is a target that can be exploited for non-invasive imaging. The expression of uPAR has been associated with phenotypically aggressive breast cancer and acquired drug-resistance. Acquired drug-resistance was modeled in cell lines from two different breast cancer subtypes, the uPAR negative luminal A subtype and the uPAR positive triple negative subtype cell line MDA-MB-231. MCF-7 cells, cultured to be resistant to tamoxifen (MCF-7 TamR), were found to significantly over-express uPAR compared to the parental cell line. uPAR expression was maintained when resistance was modeled in triple-negative breast cancer by generating doxorubicin and paclitaxel resistant MDA-MB-231 cells (MDA-MB-231 DoxR and MDA-MB-231 TaxR). Using the antagonistic uPAR antibody 2G10, uPAR was imaged in vivo by near-infrared (NIR) optical imaging and (111)In-single photon emission computed tomography (SPECT). Tumor uptake of the (111)In-SPECT probe was high in the three drug-resistant xenografts (> 46 %ID/g) and minimal in uPAR negative xenografts at 72 hours post-injection. This preclinical study demonstrates that uPAR can be targeted for imaging breast cancer models of acquired resistance leading to potential clinical applications.
authors: 1. Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94118.
authors: Aaron M
authors: AM
authors: LeBeau
authors: 2. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94118.
authors: Natalia
authors: N
authors: Sevillano
authors: 3. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901.
authors: Mandy L
authors: ML
authors: King
authors: 2. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94118.
authors: Sai
authors: S
authors: Duriseti
authors: 1. Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94118.
authors: Stephanie T
authors: ST
authors: Murphy
authors: 2. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94118.
authors: Charles S
authors: CS
authors: Craik
authors: 3. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901.
authors: Laura L
authors: LL
authors: Murphy
authors: 1. Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94118.
authors: Henry F
authors: HF
authors: VanBrocklin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D007205:Indium Radioisotopes; D061986:MCF-7 Cells; D051379:Mice; D064847:Multimodal Imaging; D061848:Optical Imaging; D017239:Paclitaxel / Q000494:pharmacology; D055293:Receptors, Urokinase Plasminogen Activator / Q000276:immunology / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D055293:Receptors, Urokinase Plasminogen Activator; D013629:Tamoxifen; D004317:Doxorubicin; D017239:Paclitaxel
keywords: drug-resistant breast cancer; human antibody; phage display.; single-photon emission computed tomography; tamoxifen resistance; urokinase plasminogen activator receptor