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Abstract
PURPOSE:
The impact of androgen receptor (AR) activity in breast cancer biology is unclear. We characterized and tested a novel therapy to an AR-governed target in breast cancer.Experimental Design: We evaluated the expression of prototypical AR gene products human kallikrein 2 (hK2) and PSA in breast cancer models. We screened 13 well-characterized breast cancer cell lines for hK2 and PSA production upon in vitro hormone stimulation by testosterone [dihydrotestosterone (DHT)]. AR-positive lines were further evaluated by exposure to estrogen (17β-Estradiol) and the synthetic progestin D-Norgestrel. We then evaluated an anti-hK2-targeted radiotherapy platform (hu11B6), labeled with alpha (α)-particle emitting Actinium-225, to specifically treat AR-expressing breast cancer xenografts under hormone stimulation.

RESULTS:
D-Norgestrel and DHT activated the AR pathway, while 17β-Estradiol did not. Competitive binding for AR protein showed similar affinity between DHT and D-Norgestrel, indicating direct AR-ligand interaction. In vivo production of hK2 was sufficient to achieve site-specific delivery of therapeutic radionuclide to tumor tissue at >20-fold over background muscle uptake; effecting long-term local tumor control.

CONCLUSIONS:
[225Ac]hu11B6 targeted radiotherapy was potentiated by DHT and by D-Norgestrel in murine xenograft models of breast cancer. AR activity in breast cancer correlates with kallikrein-related peptidase-2 and can be activated by D-Norgestrel, a common contraceptive, and AR induction can be harnessed for hK2-targeted breast cancer α-emitter radiotherapy.

Author information

Thorek DLJ1,2, Ku AT3,4, Mitsiades N5, Veach D6,7, Watson PA8, Metha D9, Strand SE10, Sharma SK11, Lewis JS6,7,11,12, Abou DS1, Lilja HG13,14,15, Larson SM6,7,12,15, McDevitt MR6,7, Ulmert D16,12,17,18,19
1
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
2
Department of Biomedical Engineering, Washington University, St. Louis, Missouri.
3
Division of Clinical Chemistry, Department of Translational Medicine, Lund University, Lund, Sweden.
4
Clinical Research Center, Lund University, Malmö, Sweden.
5
Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
6
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Department of Radiology, Weill Cornell Medical College, New York, New York.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
10
Division of Oncology and Pathology, and Medical Radiation Physics, Department of Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
11
Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
12
Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
13
Departments of Laboratory Medicine, Surgery and Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
14
Nuffield Department of Surgical Sciences, Oxford University, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
15
Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
16
Division of Oncology and Pathology, and Medical Radiation Physics, Department of Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden. HUlmert@mednet.ucla.edu.
17
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, California.
18
Jonsson Comprehensive Cancer Center, David Geffen UCLA School of Medicine, Los Angeles, California.
19
Ahmanson Translational Imaging Division, David Geffen UCLA School of Medicine, Los Angeles, California.