Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone...

Area of Science:

• Oncology
• Endocrinology
• Molecular Biology

Background:

• Estrogen receptor (ER)-positive breast cancer often becomes resistant to standard ER-targeting therapies due to ER mutations.
• Androgen receptor (AR) is highly expressed in ER-positive breast cancers and presents a potential therapeutic target.
• Previous use of AR agonists was limited by side effects, but new tissue-selective AR modulators (SARMs) have emerged.

Purpose of the Study:

• To investigate the therapeutic potential of androgen receptor (AR) agonists, including SARMs, in ER-positive breast cancer.
• To determine if AR activation can overcome resistance to ER-targeting therapies.
• To elucidate the molecular mechanisms by which AR influences ER-positive breast cancer growth.

Main Methods:

• Utilized translational models including ER-positive breast cancer cell lines, patient-derived tissues, and patient-derived xenografts (PDX).
• Administered AR agonists, antagonists, and SARMs to assess their effects on tumor proliferation and growth.
• Analyzed changes in the ER and FOXA1 cistrome upon ligand-activated AR stimulation.

Main Results:

• AR agonists and SARMs, but not AR antagonists, significantly inhibited the proliferation and growth of ER-positive breast cancer models.
• Ligand-activated AR was shown to inhibit both wild-type and mutant ER activity.
• AR activation reprogrammed the ER and FOXA1 cistrome, leading to tumor growth inhibition.

Conclusions:

• Ligand-activated AR acts as a non-canonical inhibitor of ER signaling in ER-positive breast cancer.
• AR agonists, particularly SARMs, represent a promising and potentially safer therapeutic strategy for treating ER-positive breast cancers.
• Targeting the AR pathway offers a novel approach to overcome resistance in endocrine-resistant breast cancers.