DNA ‘switch’ uncovers new brake on breast cancer growth
Adelaide University researchers have found a DNA ‘switch’ that helps the body stop the growth of the most common form of breast cancer, providing new insights that could help with future treatments.
Up to 80% of breast cancer cases are classified as oestrogen receptor-positive (ER+) – meaning their growth is driven by the hormone oestrogen.
Previous research has shown that another hormone receptor, the androgen receptor, can act as a tumour suppressor in ER+ breast cancer. Activating the androgen receptor has shown promise as a potential treatment strategy, but scientists are still working to understand exactly how it stops cancer cells from growing.
Researchers from Adelaide University’s School of Medicine, the South Australian immunoGENomics Cancer Institute (SAiGENCI) and SAHMRI have now uncovered an important piece of that puzzle.
The team had previously identified a gene called ZBTB16 as a possible contributor to this tumour-suppressing effect, with a higher presence of the gene linked to improved survival in patients with ER+ breast cancer.
However, this new study found that changing ZBTB16 levels in breast cancer cells did not alter the ability of the androgen receptor to suppress cell growth.
Instead, the researchers identified a small regulatory region of DNA hidden within the gene that proved to be critical.
“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.”
This DNA ‘switch’, known as HRRINT3, acts as an enhancer – a section of DNA that helps control gene activity. The androgen receptor binds to this enhancer when activated by androgens, hormones that are present in both women and men.
Using CRISPR gene-editing technology, researchers deleted a small section of HRRINT3 to determine what would happen when the enhancer was removed.
“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.”
Removing the DNA 'switch’ also led to a rapid increase in other androgen receptor-positive breast and prostate cancer cell models, suggesting that it may have a broader role in restraining tumour growth across multiple androgen receptor-positive cancers.
The research has been published in the journal npj Breast Cancer and is the result of a collaboration with researchers at the University of Bordeaux in France.
“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.”
Journal
npj Breast Cancer
Method of Research
Experimental study
Subject of Research
Cells
Article Title
A functional role for an intronic enhancer of ZBTB16 in AR-mediated tumour suppression in ER+ breast cancer
Two ‘forever chemicals’ associated with higher risk of aggressive breast cancer in NIH analysis
Evidence continues to grow on how environmental factors affect women’s health
Women with higher blood levels of two common per- and polyfluoroalkyl substances, also familiarly known as PFAS, were more likely to develop estrogen receptor-negative, or ER-negative, breast cancer, according to a new study by the National Institutes of Health (NIH), part of the U.S. Department of Health and Human Services (HHS). PFAS are a large group of chemicals used in common consumer products. Often referred to as “forever chemicals,” PFAS do not break down easily in the environment and can remain in the body for years.
The study found that women with higher blood plasma levels of two of these substances, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), were associated with a higher incidence of ER-negative breast cancer. No clear association was observed between the two chemicals and breast cancer risk overall.
“Women deserve clear answers about how chemicals in their environment may affect their health,” said HHS Secretary Robert F. Kennedy, Jr. “This NIH study links two forever chemicals to a higher risk of ER-negative breast cancer and demands further investigation. Under President Trump’s leadership, we will pursue the evidence, confront environmental health risks, and give women the information they need to protect their health.”
ER-negative tumors lack receptors that allow hormone estrogen to help cancer cells grow. Compared with breast cancers that respond to hormone estrogen, ER-negative breast cancers tend to be more aggressive and have worse outcomes. Scientists know less about what raises the risk of this type of breast cancer.
“Our findings, which we confirmed using a meta-analysis of prior research, indicate that certain legacy PFAS, including PFOA and PFOS, are associated with a higher risk of ER-negative breast cancer, a more aggressive tumor type with few known risk factors,” explained NIH Stadtman Investigator Alexandra White, Ph.D., who led the study. The findings are reported in the Journal of Clinical Oncology.
NIH researchers and their collaborators measured 17 PFAS in blood, collected years before women were diagnosed with cancer. Women in the group with the highest PFOA levels had a 67% higher rate of ER-negative breast cancer than those in the lowest group. For PFOS, the rate was 93% higher, or nearly twice as high. These numbers describe relative differences between groups, not an individual woman’s chance of getting breast cancer.
The research drew on the Sister Study, led by NIH’s National Institute of Environmental Health Sciences (NIEHS). The larger study enrolled 50,884 women ages 35–74 in the United States and Puerto Rico from 2003 to 2009. None had breast cancer when they joined the Sister Study, but each had a full or half-sister who had been previously diagnosed with breast cancer. For the PFAS study, researchers included 1,609 women who developed breast cancer and a comparison sample of 2,269 women.
“These findings matter for women’s health broadly,” said first author, Che-Jung Chang, Ph.D., a former research fellow at NIH and a current researcher at DLH, a scientific research organization. “Although PFAS are persistent in the environment and in our bodies, exposure to them is still potentially modifiable, meaning people can take steps to reduce their exposure, and these findings could open new avenues for prevention.”
Because the strongest associations involved tumors without hormone receptors, the authors suggest that PFAS may affect cancer risk through other non-hormonal biologic pathways. Possible pathways include changes in gene activity or immune system. However, this study did not test those explanations. The authors say future studies should evaluate people with higher PFAS exposure and in groups more affected by ER-negative breast cancer.
Although most individuals have measurable levels of PFOA and PFOS in their bodies, these compounds have been largely phased out and replaced with new PFAS compounds. “More research is needed, particularly evaluating the risk of breast cancer associated with newer replacement PFAS chemicals,” White said.
This research was supported by NIEHS grants: Z01ES044005; Z1AES103332; and R01ES032831.
Reference: Chang CJ, Pullella K, Keil AP, et al. Per- and Polyfluoroalkyl Substance Exposure and Breast Cancer Incidence in the Sister Study. Journal of Clinical Oncology. https://doi.org/10.1200/JCO-26-00318.
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About the National Institute of Environmental Health Sciences (NIEHS): NIEHS conducts and supports research to understand how the environment affects human health. It is part of the National Institutes of Health. For more information, visit www.niehs.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
NIH...Turning Discovery Into Health®
Journal
Journal of Clinical Oncology
Article Title
Per- and Polyfluoroalkyl Substance Exposure and Breast Cancer Incidence in the Sister Study
Article Publication Date
5-Nov-2026
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