Our data show expression of two receptors selectively found in the central nervous system (CNS) are very likely to be features common to all or most breast cancer (BC), and that these receptors can potentially be targeted by polyclonal and monoclonal antibodies recognizing special features in their extracellular domain. The CNS receptors promote growth of breast cancer that can be inhibited by antagonists and antibodies. Expression of such receptors therefore not only presents us with markers, for identifying tumor in breast biopsies, and for monitoring treatment of the disease(scanning for tumor response, metastases, residual tumor), but also raises the possibility to later develop new therapies. Objective/Hypothesis: The objective of this project is to provide new methods for the imaging and treatment of breast cancer (BC). The hypothesis being tested is that identified CNS receptors expressed by BC will provide sensitive and reliable targets for better detection, monitoring, and eventual treatment.
Specific Aims : Goals are directed towards: (i) establishing the distribution and abundance in breast cancer of the two CNS receptors and their selective expression by these tumors;(ii) ascertaining the effectiveness of 99mTechnetium-labeled Fabs from available anti-receptor monoclonal antibodies to image estrogen responsive and estrogen-unresponsive BC grown in athymic mice as test animals;(iii) discerning the molecular pathways involved in tumor receptor activation and blockade;(iv) assessing the specificity of receptor blockade, and;(v) determining the effectiveness of a selected monoclonal antibody to destroy/prevent growth of estrogen-responsive and estrogen-unresponsive (triple-negative) BC grown in athymic mice. Imaging and treatment with antibodies will be compared with those using ubiquitous immunoglobulin. Fabs are small binding fragments generated from intact antibodies through enzyme cleavage. Design: These investigations will employ whole body scanning of the live animals for radioactivity that should be concentrated in the tumors, and later measurement of the levels of radioactivity in different tissues. They will also involve daily size measurements of treated tumors, affinity chromatography, immunohistochemistry of human tissues, RIA, ELISA, RT-PCR, cloning, and DNA sequencing, shRNA knockdown, Western analysis, pathology, and flow cytometry. Health Relatedness: This project promises the generation of widely available and sensitive methods that have the potential for identifying cancer in breast tissue, and monitoring treatments (evaluating tumor response, detecting residual tumor and recurrent disease, localizing metastases), in most, or all, individuals with BC. Employed approaches could also eventually lead to new and more effective treatments for patients suffering from recurrent BC.

Public Health Relevance

Our project focuses on two receptor proteins, and should provide those treating breast cancer patients, with the prospect of new and precise methods for detecting disease in tissue biopsies at an earlier time, for detecting pockets of residual metastases, and for diagnosing relapse soon after a tumor recurs. Of more significance, it is also expected to eventually lead to effective new targeted treatments for most, or all, breast cancer. Such new treatments can then be directly and closely monitored for efficacy by visualizing the receptor protein markers on the tumor.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Developmental Therapeutics Study Section (DT)
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Lively, Tracy (LUGO)
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Dartmouth College
Schools of Medicine
United States
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North, William G; Pang, Roy H L; Gao, Guohong et al. (2011) Native MAG-1 antibody almost destroys human breast cancer xenografts. Breast Cancer Res Treat 127:631-7
Keegan, Brendan P; Memoli, Vincent A; Wells, Wendy A et al. (2010) Detection of Provasopressin in Invasive and Non-invasive (DCIS) Human Breast Cancer Using a Monoclonal Antibody Directed Against the C-terminus (MAG1). Breast Cancer (Auckl) 4:15-22