Androgen receptor as therapeutic indicator for LAR-positive triple-negative breast cancer: Preclinical and clinical...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) is aggressive with limited therapeutic options.
• The luminal androgen receptor (LAR+) subtype offers a target for androgen receptor (AR)-directed therapy.
• The role of AR splice variants in response to anti-androgens like bicalutamide (Bica) and enzalutamide (Enza) is not fully understood.

Purpose of the Study:

• To investigate the effects of Bica and Enza on AR splice variants in different breast cancer subtypes.
• To assess the impact of 2D vs. 3D culture models and dihydrotestosterone (DHT) on drug response.
• To evaluate the clinical relevance of AR splice variants and nuclear AR expression in Indian TNBC patient samples.

Main Methods:

• Utilized 2D monolayer and 3D spheroid cultures of LAR+ TNBC (MDA-MB-453), AR-low TNBC (MDA-MB-231), and ER+ luminal (MCF-7) cells.
• Analyzed AR splice-variant expression, cell-cycle progression, and viability following Bica and Enza treatment.
• Performed immunohistochemistry for nuclear AR on Indian TNBC patient samples.

Main Results:

• Bica and Enza demonstrated subtype-specific effects on AR splice variants and cell-cycle progression.
• Drug responses in 3D spheroids differed significantly from 2D cultures, with DHT influencing AR signaling context-dependently.
• Nuclear AR was present in 30% of Indian TNBC samples; AR splice variant profiles, not total AR, influenced treatment outcomes.

Conclusions:

• AR splice variants exhibit diverse expression and regulation across breast cancer subtypes.
• Treatment efficacy is modulated by AR splice-variant status, ER-AR interplay, and the tumor microenvironment.
• AR splice-variant analysis is essential for personalized AR-targeted therapy strategies in breast cancer.