Study Reveals Regulatory DNA Element Involved in Breast Cancer Growth Suppression

Estrogen receptor-positive (ER+) breast cancer accounts for up to 80% of breast cancer cases, with tumor growth driven by estrogen. Although the androgen receptor can act as a tumor suppressor in ER+ breast cancer, the molecular mechanisms underlying this effect remain under investigation. Activating the androgen receptor has therefore emerged as a potential treatment strategy. New findings now identify a DNA regulatory element that may help explain how androgen receptor activity restrains breast cancer cell growth.

Researchers at Adelaide University identified HRRINT3, a small regulatory region of DNA located within the ZBTB16 gene, as a critical enhancer involved in androgen receptor-mediated growth suppression. The work was conducted in collaboration with the South Australian immunoGENomics Cancer Institute, SAHMRI, and the University of Bordeaux in France. The study was published in npj Breast Cancer.

Earlier research had identified ZBTB16 as a potential contributor to the tumor-suppressing effects of the androgen receptor, with higher levels of the gene associated with improved survival in patients with ER+ breast cancer. In the new study, however, altering ZBTB16 levels in breast cancer cells did not affect the ability of the androgen receptor to suppress cell growth. Instead, the researchers found that HRRINT3 was required for the androgen receptor to effectively restrain proliferation.

HRRINT3 functions as an enhancer, a DNA sequence that helps regulate gene activity. When activated by androgens, hormones present in both women and men, the androgen receptor binds to this enhancer and influences downstream gene activity. To investigate its role, the researchers used CRISPR gene-editing technology to delete a small section of HRRINT3 and examine how removal of the regulatory element affected androgen receptor signaling and cancer cell growth.

Deleting the DNA switch reduced the androgen receptor’s ability to suppress breast cancer cell growth and disrupted androgen receptor signaling more broadly. It also increased the activity of genes involved in cell division. Removing HRRINT3 produced a rapid increase in cell growth in other androgen receptor-positive breast and prostate cancer models, suggesting that the regulatory element may have a broader role in restraining tumor growth across androgen receptor-positive cancers.

“This discovery gives us a new piece of the puzzle in understanding how the androgen receptor suppresses ER+ breast cancer. Treatments that activate the androgen receptor are already being investigated for advanced ER+ breast cancer, so understanding the molecular machinery needed for this anti-cancer effect is important. Ultimately, this work could help us develop better ways to identify and treat patients with advanced disease who have stopped responding to hormone therapies,” said Dr. Amy Dwyer from Adelaide University’s School of Medicine.

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