DNA Regulatory Switch Helps Androgen Receptor Suppress Breast Cancer Cell Growth

Adelaide University researchers have identified a regulatory DNA switch that enables the body to curb the growth of oestrogen receptor-positive (ER+) breast cancer, the most common form of the disease. In an experimental cell study published in the journal npj Breast Cancer, the international team investigated the molecular mechanisms that allow the androgen receptor to halt tumour progression. Up to 80 percent of all breast cancer cases are classified as ER+, meaning their growth is stimulated by the hormone oestrogen.

Previous research demonstrated that another hormone receptor, the androgen receptor, can act as a tumour suppressor in ER+ breast cancer. While activating the androgen receptor has shown promise as a potential therapeutic strategy, the exact biological mechanisms controlling how it stops malignant cells from multiplying have remained unresolved. The team had previously identified a gene called ZBTB16 as a potential contributor to this tumour-suppressing process, noting that higher levels of the gene correlated with improved survival outcomes in patients with ER+ breast cancer.

In the new study, conducted by researchers from Adelaide University’s School of Medicine, the South Australian immunoGENomics Cancer Institute (SAiGENCI), SAHMRI, and the University of Bordeaux in France, the investigators found that directly altering ZBTB16 levels in breast cancer cells did not change the ability of the androgen receptor to suppress cell growth. According to Dr. Amy Dwyer from Adelaide University’s School of Medicine, the surprising finding was that ZBTB16 itself was not responsible for the growth-suppressing effect, but rather a small regulatory DNA switch embedded within the gene.

This regulatory switch, designated HRRINT3, functions as an enhancer—a section of DNA that controls gene activity. When activated by androgens, which are hormones present in both women and men, the androgen receptor binds directly to this enhancer. Using CRISPR gene-editing technology, the researchers deleted a small section of HRRINT3 to observe the effects of its absence. Following the deletion, the androgen receptor could no longer suppress breast cancer cell growth as effectively, while researchers also observed broader disruption of androgen receptor signalling and increased activity among genes that drive cell division.

Co-author Dr. Zeyad Nassar, a cancer researcher with Adelaide University’s SAiGENCI and SAHMRI, noted that the enhancer operates as part of a wider regulatory network that helps the androgen receptor keep cancer cell proliferation in check. Removing the switch also caused rapid cell growth in other androgen receptor-positive breast and prostate cancer cell models, suggesting a broader role across multiple androgen receptor-positive malignancies. With treatments activating the androgen receptor currently under investigation for advanced ER+ breast cancer, the findings offer insights that could help identify and treat patients with advanced disease who no longer respond to standard hormone therapies.

Subject of Research: DNA enhancer switch regulating androgen receptor tumour suppression in breast cancer cells

Article Title: DNA ‘switch’ uncovers new brake on breast cancer growth

Article References: DNA ‘switch’ uncovers new brake on breast cancer growth. Original publication (Bibliographic details unavailable.)

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Keywords: breast cancer, androgen receptor, gene regulation, enhancers, oncology, CRISPR, ZBTB16, HRRINT3, switch, uncovers, brake, breast