Adelaide Researchers Find DNA Switch Helping Androgen Receptor Limit Cancer Growth

Scientists have pinpointed a minor genetic regulatory segment enabling the androgen receptor to restrict the proliferation of oestrogen receptor-positive breast cancer cells.

Accounting for up to 80 percent of breast cancer cases, oestrogen receptor-positive breast cancer features tumour growth that is driven by the hormone oestrogen. Therapies blocking oestrogen signalling are frequently utilized, yet certain patients suffering from advanced disease eventually cease responding to hormone therapies, generating a demand for alternative therapeutic strategies.

Past studies have demonstrated that the androgen receptor, another type of hormone receptor, can function as a tumour suppressor within oestrogen receptor-positive breast cancer. Activating this receptor has attracted interest as a potential therapeutic strategy, but exactly how it prevents cancer cells from growing has remained unclear.

Now, researchers from Adelaide University, the South Australian immunoGENomics Cancer Institute and SAHMRI have identified a small DNA switch that plays an important role in this process. This finding expands upon previous efforts by the group, which had pointed to a gene named ZBTB16 as a possible contributor to the androgen receptor’s growth-inhibiting functions.

Higher levels of this gene had been associated with improved survival among patients with oestrogen receptor-positive breast cancer. Yet, upon modifying ZBTB16 expression levels in breast cancer cells, investigators observed that this manipulation had no impact on the androgen receptor’s capacity to curb cell multiplication.

This led investigators to examine the DNA surrounding the gene, where they identified a small regulatory region known as HRRINT3.

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.

The region acts as an enhancer, a section of DNA that helps regulate gene activity. When activated by androgens, which are hormones found in both women and men, the androgen receptor binds to this enhancer.

To understand how important HRRINT3 was to this process, researchers used CRISPR gene-editing technology to remove a small section of the DNA region. Without the enhancer, the androgen receptor became less effective at suppressing breast cancer cell growth.

Additionally, the investigators noticed a more extensive impairment of androgen receptor signaling, accompanied by heightened expression in genes linked to 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.

Dr Nassar added that the enhancer appears to be part of a wider regulatory network keeping cancer cell proliferation in check. The effect was not limited to breast cancer cells, as removing the enhancer also increased growth in other androgen receptor-positive breast and prostate cancer cell models.

This discovery emerged via a joint effort uniting investigators from Adelaide University with peers based at the University of Bordeaux, France.

Treatments that activate the androgen receptor are already being investigated for advanced oestrogen receptor-positive breast cancer. Further research will now determine how these findings translate into clinical applications, including whether the enhancer could help identify patients most likely to benefit from these therapies.