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Updated: Feb 4, 2026

Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer
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Harnessing Androgen Receptor Pathway Activation for Targeted Alpha Particle Radioimmunotherapy of Breast Cancer

Daniel L J Thorek1,2, Anson T Ku3,4, Nicholas Mitsiades5

  • 1Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 27, 2018
PubMed
Abstract

Insights

Novel therapy targets androgen receptor (AR) in breast cancer. D-Norgestrel activates AR, enabling hK2-targeted alpha-emitter radiotherapy for AR-positive tumors, showing long-term control.

Area of Science:

  • Oncology
  • Endocrinology
  • Radiotherapy

Background:

  • The role of androgen receptor (AR) in breast cancer remains incompletely understood.
  • Targeting AR offers a potential therapeutic strategy for specific breast cancer subtypes.

Purpose of the Study:

  • To characterize AR activity in breast cancer models.
  • To evaluate a novel alpha-emitter radiotherapy targeting human kallikrein 2 (hK2) in AR-expressing breast cancer.

Main Methods:

  • Screened 13 breast cancer cell lines for hK2 and PSA production after in vitro hormone stimulation (DHT).
  • Assessed AR-positive lines with estrogen (17β-Estradiol) and D-Norgestrel.
  • Evaluated an anti-hK2 radiotherapy platform ([225Ac]hu11B6) in hormone-stimulated AR-expressing breast cancer xenografts.

Main Results:

  • D-Norgestrel and dihydrotestosterone (DHT) activated the AR pathway; 17β-Estradiol did not.
  • DHT and D-Norgestrel demonstrated similar binding affinity to AR protein.
  • In vivo hK2 production enabled targeted delivery of Actinium-225 radionuclide to tumor tissue, achieving >20-fold uptake over background and long-term local tumor control.

Conclusions:

  • AR activity in breast cancer correlates with kallikrein-related peptidase-2 (hK2).
  • D-Norgestrel, a common contraceptive, can activate AR and potentiate targeted radiotherapy.
  • AR induction can be leveraged for hK2-targeted alpha-emitter radiotherapy in breast cancer treatment.

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