Australian researchers have identified a surprising role for an important cancer-fighting protein.
Researchers from the Peter MacCallum Cancer Centre have discovered an unexpected role for the retinoblastoma protein, long thought to be a “natural brake” on cancer growth.
The Rb protein has historically been thought to help protect us from breast cancer by stopping cells from dividing uncontrollably. Patients with hormone receptor-positive breast cancer – the most common breast cancer subtype – are treated with CDK4/6 inhibitors, which activates the Rb protein and slows cancer growth. While CDK4/6 inhibitors are effective initially, many cancers eventually become resistant.
Now, researchers at Peter Mac have found that while Rb switches cell division-driving genes off, it also activates other oestrogen-sensitive genes – some of which help cancer cells develop resistance to treatment and eventually start growing again.
Their findings were published in Nature.
The researchers showed that CDK4/6 inhibition enhances oestrogen receptor target gene expression in breast cancer cells, patient-derived xenografts, and clinical hormone receptor-positive breast cancer samples. This activity is partly mediated by KDM5A, which interacts with the Rb protein to affect gene regulation.
Associate Professor Shom Goel, the senior author on the new research, said the findings would change the way that the Rb protein was viewed in the context of cancer.
“We’ve always viewed Rb as a straightforward tumour suppressor that puts the brakes on cancer cell growth,” he told media.
“Our study shows that the story is far more nuanced. While Rb continues to block cell division, it can also switch on biological programs that partially work against its own protective effects.”
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Professor Goel also said that the findings offered an explanation as to why CDK4/6 inhibitors and endocrine therapy work well in combination.
“These treatments complement each other remarkably well,” he said.
“The CDK4/6 inhibitor activates Rb to stop cancer cells dividing, while endocrine therapy blocks the unwanted oestrogen-driven signals that Rb can also trigger. Together, they allow the tumour-suppressing effects of Rb to dominate.”
However, problems begin to occur when the cancer becomes resistant to endocrine therapy. In this scenario, the effectiveness of CDK4/6 inhibitors is reduced because the oestrogen-related gene program continues to operate.
“Understanding this previously unknown role of Rb gives us an important new way to think about drug resistance,” Professor Goel said.
“We hope these insights will guide the development of new combination therapies that keep these treatments working for longer and ultimately improve outcomes for people with breast cancer.”
Professor Goel emphasised that this research would change the broader context of how tumour suppressors are viewed.
“We tend to divide cancer proteins into good actors and bad actors. But our findings show that even a protein whose main role is to prevent cancer can have other effects that help tumour cells adapt to treatment,” he said.
“That opens up a new way of understanding how tumour suppressors work, and how we might target their less helpful effects without losing their protective activity.”
