Researchers at Adelaide University have identified a small regulatory region of DNA that helps the body restrict the growth of oestrogen receptor-positive (ER+) breast cancer. The discovery offers new insights into how the androgen receptor suppresses cancer cell proliferation and could inform the development of future treatments for patients with advanced breast cancer.
Published in npj Breast Cancer, the study identifies a DNA enhancer called HRRINT3 that plays an important role in the tumour-suppressing activity of the androgen receptor. The research was conducted by scientists from Adelaide University’s School of Medicine, the South Australian immunoGENomics Cancer Institute (SAiGENCI) and SAHMRI, in collaboration with researchers at the University of Bordeaux in France.
DNA Regulatory Region Plays a Key Role in Controlling Breast Cancer Growth
Up to 80% of breast cancer cases are classified as oestrogen receptor-positive, meaning that the growth of these tumours is driven by the hormone oestrogen.
Previous research has shown that the androgen receptor, another hormone receptor present in both women and men, can help suppress tumour growth in ER+ breast cancer. Although activating this receptor has emerged as a potential treatment strategy, scientists have been investigating the molecular mechanisms behind its effects.
The Adelaide University team had previously identified a gene called ZBTB16 as a possible contributor to this process. Higher levels of the gene had also been associated with improved survival among patients with ER+ breast cancer.
However, the latest research found that altering ZBTB16 levels in breast cancer cells did not change the androgen receptor’s ability to restrict cell growth. Instead, scientists discovered that a small regulatory DNA region located within the gene was responsible for an important part of this effect.
“The surprising finding was that ZBTB16 itself was not responsible for the growth-suppressing effect,” said Dr Amy Dwyer from Adelaide University’s School of Medicine.
“Instead, we found that a small DNA ‘switch’ sitting inside the gene helps the androgen receptor to restrain cancer cell growth.”
CRISPR Experiments Reveal How the HRRINT3 Enhancer Works
The identified DNA region, known as HRRINT3, functions as an enhancer, a regulatory section of DNA that helps control gene activity. When activated by androgens, the androgen receptor binds to this region and contributes to the suppression of cancer cell growth.
To investigate its function, researchers used CRISPR gene-editing technology to remove a small section of HRRINT3 from breast cancer cells.
The results showed that removing the enhancer weakened the androgen receptor’s ability to suppress cell proliferation. Researchers also observed disruption in broader androgen receptor signalling and increased activity among genes associated with cell division.
“When we deleted this DNA ‘switch’, the androgen receptor could no longer suppress breast cancer cell growth as effectively,” said co-author Dr Zeyad Nassar, a cancer researcher with Adelaide University’s SAiGENCI and SAHMRI.
“We also observed broader disruption of androgen receptor signalling and increased activity of genes that drive cell division.
“This tells us that the enhancer is doing much more than simply controlling ZBTB16. It appears to be part of a wider regulatory network that helps the androgen receptor keep cancer cell proliferation in check.”
The researchers also observed increased growth in other androgen receptor-positive breast and prostate cancer cell models after removing the DNA enhancer. This suggests that HRRINT3 may have a broader role in regulating tumour growth across different types of androgen receptor-positive cancers.
Findings Could Inform Future Breast Cancer Treatments
The discovery provides a clearer understanding of the molecular mechanisms through which the androgen receptor helps control ER+ breast cancer growth.
Treatments designed to activate the androgen receptor are already being investigated for advanced ER+ breast cancer. Understanding the DNA regulatory mechanisms required for this tumour-suppressing effect could help researchers improve these treatment approaches.
“This discovery gives us a new piece of the puzzle in understanding how the androgen receptor suppresses ER+ breast cancer,” Dr Dwyer said.
“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.”
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